担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Psoriasis is characterized by T-helper 17 cell-dominant abnormal immunity, and hyperproliferation and abnormal differentiation of epidermal keratinocytes. Some patients are associated with arthritis. Dietary habits can modulate the pathogenesis of psoriasis. Previous studies in Western countries showed higher body mass indices, higher intake of fat and lower intake of fish or vegetables in psoriatic patients compared with the reference groups. We evaluated dietary habits in adult Japanese psoriatic patients, using a validated brief-type self-administered dietary history questionnaire, and compared the results to those of age- and sex-matched healthy controls. The results in psoriatic patients with arthritis were compared with those in the patients without. Japanese psoriatic patients showed higher body mass indices, higher intake of fish/shellfish, pulses, sugar/sweeteners, vitamin B12 and vitamin D, and lower intake of meat, compared with those of healthy controls. The logistic regression analysis showed that psoriasis was associated with high body mass index and low intake of meat. The intake of confection in patients with high Psoriasis Area and Severity Index was higher than that in those with low index. The intake of β-carotene, vitamin A and green/yellow vegetables in psoriatic patients with arthritis were higher than those in the patients without. The dietary habits in Japanese psoriatic patients are rather different from those in Western patients. This is the first study showing the differences in dietary habits between psoriatic patients with arthritis and those without. Further studies should elucidate the relationships of these results with skin and joint lesions in psoriatic patients.

DOI： 10.1111/1346-8138.15032

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dietary habits can modulate the pathogenesis of atopic dermatitis. We evaluated these habits in adult Japanese patients with atopic dermatitis using a validated, brief-type self-administered diet history questionnaire and compared the results to those of age- and sex-matched healthy controls. Patients with atopic dermatitis showed higher intakes of carbohydrate and potatoes and lower intakes of alcohol, niacin, meat and oils/fats compared with those of the healthy controls. The results of logistic regression analysis showed that the intake of alcohol was negatively associated with atopic dermatitis (odds ratio, 0.905; 95% confidence interval, 0.832-0.983; P = 0.0181). The intakes of vitamin B6 and fruit were positively correlated with the severity scoring of atopic dermatitis. Multiple regression analysis revealed that vitamin B6 intake was a predictor of the severity scoring of atopic dermatitis (β = 26.98508709, t = 2.3995292, P = 0.01933781). The intakes of vegetable fat, n-6 polyunsaturated fatty acid, and confections were lower in the severe atopic dermatitis group (severity scoring of atopic dermatitis, ≥33) than those in the mild group. Atopic dermatitis is negatively associated with alcohol intake, and intake of vitamin B6 is a predictor of severity scoring of atopic dermatitis. The intake of n-6 polyunsaturated fatty acid is lower in the severe atopic dermatitis group than that in the mild group. Further study is warranted on the relationships of these results with abnormal immune responses, impaired skin barrier or pruritus in atopic dermatitis.

DOI： 10.1111/1346-8138.14881

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ajpath.2013.01.044

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS INC  

Psoriasis patients are frequently associated with metabolic syndromes. Such associations are possibly mediated by adipokines. We investigated the in vitro effects of visfatin (an adipokine) on chemokine expression in human keratinocytes. Normal human keratinocytes were incubated with visfatin, and their chemokine production was analyzed by ELISA and RT-PCR. Visfatin enhanced TNF-alpha-induced CXC chemokine ligand (CXCL) 8, CXCL10, and CC chemokine ligand (CCL) 20 secretion and mRNA expression in keratinocytes, although visfatin alone was ineffective. A small interfering RNA against nuclear factor-kappa B (NF-kappa B) p65 suppressed the visfatin-induced production of CXCL8, CXCL10, and CCL20 whereas a small interfering RNA against signal transducer and activator of transcription (STAT) 3 suppressed CXCL8 induction. This indicates the involvement of NF-kappa B in CXCL8, CXCL10, and CCL20 induction by visfatin and the involvement of STAT3 in CXCL8 induction. Visfatin alone increased the transcriptional activity and tyrosine phosphorylation of STAT3, which was suppressed by Janus kinase (JAK) 2 inhibitor. Visfatin enhanced basal and TNF-alpha-induced NF-kappa B activity and inhibitory kappa B (I kappa B) alpha phosphorylation, which was suppressed by I kappa B kinase inhibitor. Visfatin induced the tyrosine and serine phosphorylation of JAK2 and I kappa B kinase alpha/beta, respectively. Intraperitoneal injection of visfatin elevated mRNA and protein levels of CXCL1, CXCL10, and CCL20 in murine skin. These results suggest that visfatin enhances CXCL8, CXCL10, and CCL20 production in human keratinocytes and homologous chemokine production in murine skin. Visfatin may induce the infiltration of type 1 or type 17 helper T cells or neutrophils to the skin via chemokine induction and thus link metabolic syndromes to psoriasis. (Endocrinology 152: 3155-3164, 2011)

DOI： 10.1210/en.2010-1481

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/en.2008-0343

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MOSBY, INC  

Background: The chemokine CCL27 attracts skin-homing T cells. CCL27 production by keratinocytes is dependent on nuclear factor kappa B (NF-kappa B) activity and enhanced in lesions of patients with atopic dermatitis, psoriasis vulgaris, or allergic contact dermatitis. IL-17 is released from activated memory T cells and modulates skin inflammation.
Objective: We examined the in vitro effects of IL-17 on TNF-alpha-induced CCL27 production in human keratinocytes.
Methods: Keratinocytes were incubated with TNF-alpha, IL-17, or both. CCL27 secretion and mRNA levels were analyzed by means of ELISA and RT-PCR, respectively. COX-2 promoter and NF-kappa B activities were analyzed by using luciferase assays. COX-2 protein levels were analyzed by means of Western blotting.
Results: IL-17 suppressed TNF-alpha-induced CCL27 secretion and mRNA expression and NF-kappa B activity in keratinocytes. The COX-2 inhibitor NS398 counteracted the effects of IL-17, and prostaglandin E-2 prevented counteraction by NS398. IL-17 alone or synergistically with TNF-alpha increased prostaglandin E2 release from keratinocytes, and the increase was suppressed by NS398. IL-17 alone or synergistically with TNF-alpha increased COX-2 mRNA and protein levels, promoter activity, and mRNA stability. The stimulatory effects of IL-17 on COX-2 expression were suppressed by inhibitors of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) kinase. IL-17 alone or synergistically with TNF-a induced dual phosphorylation of p38 MAPK and ERK.
Conclusion: IL-17 might suppress TNF-alpha-induced CCL27 production by inhibiting NF-kappa B through induction of COX-2. The induction of COX-2 might be mediated by activation of p38 MAPK and ERK. T cell-derived IL-17 might alleviate T-cell skin infiltration through inhibition of CCL27 production.

DOI： 10.1016/j.jaci.2005.08.014

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI IRELAND LTD  

Recent studies have revealed that sex hormones manifest a variety of biological and immunological effects in the skin. Pregnancy, menstruation and the menopause modulate the natural course of psoriasis, indicating a female hormone-induced regulation of skin inflammation. Estrogen in vitro down-regulates the production of the neutrophil, type 1 Tcell and macrophage-attracting chemokines, CXCL8, CXCL10, CCL5, by keratinocytes, and suppressesIL-12 production and antigen-presenting capacity white enhancing anti-inflammatory IL-10 production by dendritic cells. These data indicate that estrogen may attenuate inflammation in psoriatic lesions. Estrogen, alone or together with progesterone, prevents or reverses skin atrophy, dryness and wrinkles associated with chronological or photo-aging. Estrogen and progesterone stimulate proliferation of keratinocytes white estrogen suppresses apoptosis and thus prevents epidermal atrophy. Estrogen also enhances collagen synthesis, and estrogen and progesterone suppress collagenolysis by reducing matrix metalloproteinase activity in fibroblasts, thereby maintaining skin thickness. Estrogen maintains skin moisture by increasing acid mucopolysaccharide or hyaluronic acid levels in the dermis. Progesterone increases sebum secretion. Estrogen accelerates cutaneous wound heating stimulating NGF production in macrophages, GM-CSF production in keratinocytes and bFGF and TGF-beta 1 production in fibroblasts, leading to the enhancement of wound re-innervation, re-epithelialization and granulation tissue formation. In contrast, androgens prolong inflammation, reduce deposition of extracellular matrix in wounds, and reduce the rate of wound heating. Estrogen enhances VEGF production in macrophages, an effect that is antagonized by androgens and which may be related to the development of granuloma pyogenicum during pregnancy. These regulatory effects of sex steroids may be manipulated as therapeutic or prophylactic measures in psoriasis, aging, chronic wounds or granuloma pyogenicum. (c) 2004 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.jdermsci.2004.10.011

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MOSBY, INC  

Background: The chemokine CCL27 attracts skin-homing T cells. CCL27 production by keratinocytes is enhanced in skin lesions from patients with atopic dermatitis or psoriasis vulgaris. It is suggested that prostaglandin E-2 (PGE(2)) regulates skin inflammation.
Objective: We examined the in vitro effects of PGE(2) On CCL27 production in human keratinocytes.
Methods: Keratinocytes were incubated with TNF-alpha in the presence or absence of PGE(2)-CCL27 secretion and mRNA level were analyzed by means of ELISA and RT-PCR, respectively. Nuclear factor kappaB (NF-kappaB)-dependent transcriptional activity was analyzed by using luciferase assays.
Results: TNF-alpha increased CCL27 secretion and mRNA levels in parallel to NF-kappaB activity in keratinocytes. NF-kappaB p50 or p65 antisense oligonucleotides suppressed TNF-alpha-induced CCL27 production, indicating the requirement of NF-kappaB for CCL27 production. PGE(2), EP2, or EP3 agonists reduced TNF-alpha-induced CCL27 secretion and mRNA levels in parallel to NF-kappaB activity and CCL2, CCL5, CXCL8, and CXCLIO mRNA levels. Either EP3-specific or dual EP1-EP2 antagonist partially blocked the inhibitory effects of PGE(2) on CCL27 production and NF-KB activity, and the addition of both completely abrogated the inhibition, whereas EP1 or EP4 antagonists were ineffective. Intracellular Ca2+ chelator BAPTA/AM or cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor H-89 partially blocked the inhibitory effects of PGE(2) on CCL27 production and NF-KB activity, and the addition of both completely abrogated the inhibition. PGE(2) or EP3 agonist increased intracellular Ca2+ concentrations. PGE(2) or EP2 agonist increased intracellular cAMP concentrations.
Conclusion: PGE(2) might suppress CCL27 production by inhibiting NF-KB activity through EP2-mediated cAMP and EP3-mediated Ca2+ signals. PGE(2) might terminate T cellmediated skin inflammation by inhibiting CCL27 production.

DOI： 10.1016/j.jaci.2004.08.041

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

Gangliosides are sialic acid-containing glycolipids. We studied the in vitro effects of gangliosides on Th1 and Th2 cytokine production in PHA-stimulated human T cells. Gangliosides GD1b, GT1b, and GQ1b (each 100 nM) enhanced PHA-induced IL-2 secretion of peripheral blood T cells similar to4-fold and enhanced that of IFN-gamma 3- to 4-fold compared with controls. These gangliosides decreased PHA-induced IL-4 secretion by 50-53% and that of IL-5 by 53-63% compared with controls, respectively. The other gangliosides did not alter the secretion of Th1 or Th2 cytokines, RT-PCR showed that GD1b, GT1b, and GQ1b enhanced PHA-induced IL-2 and IFN-gamma transcription and suppressed that of IL-4 and IL-5. Transient transfection assays of Jurkat T cells showed that GD1b, GT1b, and GQ1b enhanced PHA-induced IL-2 and IFN-gamma promoter activities but suppressed those of IL-4 and IL-5, The cAMP analogue dibutyryl cAMP and the cAMP-elevating agents forskolin and 3-isobutyl-1-methylxanthine each reversed GD1b-, GT1b-, and GQ1b-induced stimulation of IL-2 and IFN-gamma production and inhibition of IL-4 and IL-5 production at the levels of proteins, transcription, and promoter activities. GD1b, GT1b, and GQ1b suppressed PHA-induced increase in cAMP level in T cells. These gangliosides suppressed PHA-stimulated adenylate cyclase activity in T cells, These results suggest that GD1b, GT1b, and GQ1b may enhance Th1 cytokine production while suppressing Th2 production by inhibiting adenylate cyclase activity.

DOI： 10.4049/jimmunol.166.1.72

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MOSBY, INC  

Background: previously, we reported that ganglioside GQ1b greatly enhanced spontaneous immunoglobulin production in vitro by PBMCs from normal human subjects.
Objective: We examined in vitro effects of GQ1b on anti-double-stranded DNA (anti-dsDNA) antibody production by PBMCs from patients with systemic lupus erythematosus (SLE).
Methods: PBMCs from patients with SLE were cultured with GQ1b, IgG anti-dsDNA antibody, total Igc, and cytokine amounts in the culture supernatants and protein kinase C (PKC) activity of T cells were measured by using ELISA.
Results: GQ1b enhanced both anti-dsDNA and total Ige production of PBMCs from patients with SLE who were seropositive for anti-dsDNA. Among the seropositive patients, the active patients were more responsive to GQ1b in anti-dsDNA production than the inactive patients. GQ1b also enhanced total Ige production of PBMCs from patients with SLE who were seronegative for anti-dsDNA but did not induce their anti-dsDNA production. In contrast to PBMCs, GQ1b did not affect the antibody production either of purified CD5(+) or of CD5(-) B cells, Anti-IL-6 or anti-IL-10 antibody each partially blocked the GQ1b-induced enhancement of antibody production in PBMCs, and the addition of both antibodies completely blocked the enhancement. GQ1b increased IL-6 and IL-10 production of T cells. The supernatant from GQ1b-treated T cells enhanced antibody production both of CD5(+) and of CD5-B cells to a greater extent than that from medium-treated T cells, Exogenous IL-6 and IL-10 additively increased the antibody production both of CD5(+) and CD5- B cells. CQ1b-induced increases in IL-6 and IL-IO production of T cells Here both blocked by PKC inhibitors, calphostin C and staurosporine. GQ1b enhanced PKC activity of T cells.
Conclusion: These results suggest that GQ1b may polyclonally increase the production of IgG, including IgG anti-dsDNA antibody, in PBMCs from patients with SLE by promoting IL-6 and IL-10 production of T cells through the enhancement of their PKC activity.

DOI： 10.1067/mai.2000.104253

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担当区分：筆頭著者,　責任著者   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MOSBY-YEAR BOOK INC  

Background: Gangliosides are glycosphingolipids that contain sialic acid and have various immunomodulatory effects. Objective: We studied in vitro effects of gangliosides on human humoral immune responses, Methods: PBMCs from healthy volunteers were cultured with gangliosides GM1, GM2, GM3, GD1a, GD1b, GD2, GD3, GT1b, and GQ1b, The amounts of IgG, IgM, and IgA and cytokine activity in the culture supernatants were measured with use of an ELISA, Proliferation was determined by [H-3] thymidine uptake, Results: Among the various gangliosides tested, GQ1b most strongly enhanced spontaneous IgG, IgM, and IgA production by human PBMCs. The effect of GQ1b was revealed at 0.1 mu mol/L, increased dose dependently, and was maximized at 10 mu mol/L. Weaker but significant stimulatory effects on the Ig production were manifested by GM2 and GD1a, whereas GT1b and GD1b were inhibitory. None of the gangliosides examined affected the proliferation of PBMCs. GQ1b did not enhance Ig production of B cells alone, Anti-IL-6 and anti-IL-10 antibody each partially blocked GQ1b-induced enhancement of the Ig production by PBMCs, and the addition of both antibodies completely blocked the enhancement. GQ1b enhanced both IL-6 and IL-10 production of T cells without affecting those of monocytes or B cells. GQ1b enhanced Ig production of T and B cell culture without monocytes. When T cells were preincubated with GQ1b, washed and added to B cells and monocytes, and then cultured together the Ig production was also enhanced, although to a lesser extent than the whole time incubation. Exogenous IL-6 and IL-10 each enhanced Ig production of B cells alone, and the addition of both gave additive effects, Conclusion: These results suggest that GQ1b mag indirectly enhance Ig production of B cells bg promoting IL-6 and IL-10 production of T cells in whole PBMC culture. That GQ1b may act as an important immunostimulator is also indicated.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT-RAVEN PUBL  

Objective. To study the in vitro effect of testosterone on anti-DNA antibody production in peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE) in order to elucidate its regulatory role in SLE.
Methods, PBMC from SLE patients were cultured with testosterone. IgG anti-double-stranded DNA (anti-dsDNA) antibody, total IgG, and cytokine activity in the supernatants were measured by enzyme-linked immunosorbent assay.
Results, Testosterone suppressed both IgG anti-dsDNA antibody and total IgG production in PBMC from SLE patients, Antibody production in B cells was also suppressed by testosterone, although the magnitude of its effect on B cells was lower than that on PBMC, Interleukin-6 (IL-6) partially restored the testosterone-induced decrease in antibody levels in PBMC, Testosterone reduced IL-6 production in monocytes,
Conclusion. These results suggest that testosterone may directly suppress anti-DNA antibody production in PBMC from SLE patients by inhibiting B cell hyperactivity and, indirectly, by down-regulating IL-6 production in monocytes, These results support the therapeutic effects of testosterone on SLE.

DOI： 10.1002/art.1780400921

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Janus kinase 1 inhibitor upadacitinib is therapeutically effective for atopic dermatitis (AD). However, predictive factors for high responders to upadacitinib have not been established in real-world clinical practice. OBJECTIVES: To identify predictive factors for responders to upadacitinib 15 mg or 30 mg, defined as achievers of investigator's global assessment (IGA) 0/1 with ≥ 2-point improvement from basal IGA. METHODS: A retrospective study was conducted from August 2021 to July 2023 on 159 AD patients treated with upadacitinib 15 mg and 52 patients with 30 mg. Patients in each group were categorized into responders (achievers of IGA 0/1 at week 12) and non-responders (non-achievers). We compared baseline values of clinical and laboratory parameters between responders and non-responders. Logistic regression analysis was used to detect variables predicting responders. Receiver-operating characteristic curves were used for evaluating prediction capabilities of the variables. RESULTS: In logistic regression analysis, responders to 15 mg upadacitinib were associated with lower total EASI and higher age whereas responders to 30 mg were associated with lower LDH and lower IgE. CONCLUSIONS: Lower total EASI and higher age may predict responders to upadacitinib 15 mg while lower IgE and lower LDH may predict responders to 30 mg.

DOI： 10.1080/09546634.2024.2310643

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Though Janus kinase inhibitors such as upadacitinib rapidly relieve itch in atopic dermatitis (AD) patients, how early itch relief impacts later skin clearance is not examined. OBJECTIVES: This study aims to determine if early itch relief by upadacitinib could predict complete skin clearance in later phases. METHODS: This retrospective study involved 105 patients with moderate-to-severe AD treated with upadacitinib 15 mg/day. Eczema area and severity index (EASI), atopic dermatitis control tool, and achievement rate of EASI 100 were evaluated at weeks 4, 12, and 24. The threshold of early peak pruritus-numerical rating scale (PP-NRS) predicting later skin clearance was assessed by area under the receiver-operating characteristic curve, and predictors for EASI 100 achievement were determined by logistic regression analysis. RESULTS: The rate of achieving EASI 100 at week 24 was extremely higher in patients who achieved week 2 PP-NRS ≤ 1 (42.9%) than in non-achievers (1.4%). The logistic regression analysis showed that the achievement of week 2 PP-NRS ≤ 1 and low body mass index were associated with achievement of EASI 100 at weeks 12 and 24. CONCLUSIONS: The achievement of week 2 PP-NRS ≤ 1 may predict later skin clearance in upadacitinib treatment.

DOI： 10.1080/09546634.2023.2291317

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vitiligo is an autoimmune skin disease with acquired depigmentation. Dietary habits may modulate the pathogenesis of vitiligo. We evaluated dietary habits in adult Japanese patients with nonsegmental vitiligo, and compared their results with those of age- and sex-matched controls. We also examined the relationship between dietary habits and Vitiligo Area Scoring Index (VASI), or vitiligo on different anatomical sites. The intakes of energy, nutrients, and foods in the participants were analyzed using a brief-type self-administered diet history questionnaire. Patients with vitiligo showed higher body mass index (BMI) and lower intakes of manganese, vitamin D, pulses, and confection, compared with controls. Multivariate logistic regression analysis showed that vitiligo was associated with high BMI. VASI was higher in males than in females, and negatively correlated with age or intakes of potatoes and vegetables other than green/yellow vegetables. Linear multivariate regression analysis showed that high VASI was associated with younger age. Multivariate logistic regression analysis showed that moderate to severe vitiligo (VASI ≥ 4.25) was associated with male sex and longer disease duration. Multivariate logistic regression analyses showed the following association with vitiligo on respective anatomical sites: high intake of eggs and dairy products and high VASI on the head or neck, high intake of oils and fats and high VASI on the trunk, high intake of cereals and high VASI on the upper limbs, male sex and high VASI on the lower limbs, and high BMI and high VASI on the hands or feet. In conclusion, the control of obesity might have prophylactic or therapeutic effects on vitiligo.

DOI： 10.1111/1346-8138.17163

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Upadacitinib is an oral Janus kinase (JAK) 1 inhibitor approved in Japan for moderate-to-severe atopic dermatitis (AD), and it provides a high therapeutic efficacy. OBJECTIVES: We compared the therapeutic effects of upadacitinib on skin rashes of individual anatomical sites, head and neck, upper limbs, lower limbs, and trunk in patients with AD. METHODS: From August 2021 to December 2022, 65 Japanese patients with moderate-to-severe AD (aged ≥ 12 years) were treated with oral once daily upadacitinib 15 mg plus twice daily topical corticosteroids of moderate-to-strongest classes. RESULTS: The eczema area and severity indexes (EASIs) of individual sites decreased significantly at weeks 4, 12, and 24 compared to those at week 0 in parallel to total (whole body) EASI. The achievement rates of EASI 75 at week 24 and of EASI 90 at week 12 of lower limbs were significantly higher than those of trunk. The percent reductions of EASI of lower limbs at weeks 12 and 24 were significantly higher than those of head and neck and of trunk. CONCLUSIONS: Among the four anatomical sites, the treatment responsiveness to upadacitinib in lower limbs appeared the highest, while those in trunk and in head and neck appeared relatively lower.

DOI： 10.1080/09546634.2023.2212095

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Atopic dermatitis (AD) is a chronic eczematous disease with severe pruritus. Janus kinase (JAK) inhibitors, upadacitinib, baricitinib, and abrocitinib, are systemic treatments for AD. The outcomes of switching from one JAK inhibitor to another have not been examined. OBJECTIVES: We assessed the outcomes of switching from baricitinib 4 mg to upadacitinib 30 mg in Japanese patients with moderate-to-severe AD. METHODS: Twenty patients treated with baricitinib 4 mg, showing insufficient response or adverse events, were switched to treatment with upadacitinib 30 mg. We evaluated total eczema area and severity index (EASI), EASI at head and neck, trunk, upper, or lower limbs, EASI of erythema, edema/papulation, excoriation, or lichenification, and peak pruritus numerical-rating scale (PP-NRS) at baseline (start of baricitinib), weeks 0 (time of switching), and 4 and 12 after switching. RESULTS: Total EASI, EASI at each anatomical site, EASI of each clinical sign, and PP-NRS were markedly reduced at weeks 4 or 12 compared to week 0. Achievement rates of more than 75% or 90% reduction of EASI from baseline significantly improved after switching. CONCLUSIONS: Switching from baricitinib 4 mg to upadacitinib 30 mg effectively improved rash and pruritus.

DOI： 10.1080/09546634.2023.2276043

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Atopic dermatitis (AD) is a chronic eczematous disease with various types of rash, erythema, edema/papulation, excoriation, or lichenification. Janus kinase 1 inhibitor upadacitinib is effective for moderate-to-severe AD. We aimed to investigate the therapeutic effects of upadacitinib on each rash type in AD patients in real-world clinical practice. Seventy-two Japanese patients with moderate-to-severe AD were treated with oral upadacitinib 15 mg/day plus topical corticosteroids. The Eczema Area and Severity Index (EASI) scores for erythema, edema/papulation, excoriation, or lichenification on the whole body or on head and neck, upper limbs, lower limbs, or trunk were assessed at weeks 0, 4, and 12 of treatment. The proportions of patients who achieved resolution or at least 75% reduction of EASI from baseline (EASI 75) for individual rash types were calculated at weeks 4 and 12 on the whole body or each anatomical site. The resolution rates for excoriation, erythema, edema/papulation, or lichenification on the whole body were 38.3%, 23.7%, 21.7%, and 8.3% at week 4 and 18.3%, 18.6%, 11.6%, and 13.3% at week 12, respectively. The EASI scores for all rash types significantly decreased at weeks 4 and 12 compared to week 0. The achievement rates of EASI 75 for excoriation, erythema, edema/papulation, or lichenification on the whole body were 67.2%, 66.7%, 49.2%, and 37.7% at week 4 and 57.3%, 65%, 41%, and 41% at week 12, respectively. The achievement rate of EASI 75 for erythema on head and neck at week 4 (45.3%) was lower than that on upper limbs (71%) and on lower limbs (70.8%), and that on head and neck at week 12 (42.2%) was lower than that on lower limbs (69.2%). These results indicate that upadacitinib is effective for all AD rash types, especially for excoriation and erythema, while head-and-neck erythema might be less responsive to upadacitinib.

DOI： 10.1111/1346-8138.16950

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Upadacitinib is an oral Janus kinase (JAK) 1 inhibitor approved in Japan for moderate-to-severe atopic dermatitis (AD), and it provides a high therapeutic efficacy. OBJECTIVES: We compared the therapeutic effects of upadacitinib on skin rashes of individual anatomical sites, head and neck, upper limbs, lower limbs, and trunk in patients with AD. METHODS: From August 2021 to December 2022, 65 Japanese patients with moderate-to-severe AD (aged ≥ 12 years) were treated with oral once daily upadacitinib 15 mg plus twice daily topical corticosteroids of moderate-to-strongest classes. RESULTS: The eczema area and severity indexes (EASIs) of individual sites decreased significantly at weeks 4, 12, and 24 compared to those at week 0 in parallel to total (whole body) EASI. The achievement rates of EASI 75 at week 24 and of EASI 90 at week 12 of lower limbs were significantly higher than those of trunk. The percent reductions of EASI of lower limbs at weeks 12 and 24 were significantly higher than those of head and neck and of trunk. CONCLUSIONS: Among the four anatomical sites, the treatment responsiveness to upadacitinib in lower limbs appeared the highest, while those in trunk and in head and neck appeared relatively lower.

DOI： 10.1080/09546634.2023.2212095

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Upadacitinib, an oral Janus kinase 1 inhibitor approved for treating atopic dermatitis (AD), can cause adverse events such as herpes zoster (HZ) and acne. We aimed to identify background factors predicting the occurrence of HZ and acne during upadacitinib treatment in patients with AD. From August 2021 to December 2022, 112 Japanese patients with moderate-to-severe AD (aged ≥12 years) were treated with upadacitinib 15 mg/day (78 patients) or 30 mg/day (34 patients) plus topical corticosteroids or delgocitinib limited to head and neck for 3-9 months. AD patients with the occurrence of HZ during upadacitinib treatment had higher incidences for history of HZ and of bronchial asthma than those without in the upadacitinib 15 mg, 30 mg, and whole groups. AD patients with occurrence of HZ had higher pretreatment values of lactate dehydrogenase and eczema area and severity index on head and neck compared to those without in the upadacitinib 15 mg and whole groups. Logistic regression analysis revealed that history of HZ was associated with the occurrence of HZ in the upadacitinib 15 mg and whole groups. The proportion of underage patients (<18 years) was higher in patients with occurrence of acne compared to those without in the upadacitinib 30 mg group, but no significant differences were found in the other background factors between the two patient populations. History of HZ may predict the occurrence of HZ during upadacitinib treatment in patients with AD.

DOI： 10.1111/1346-8138.16879

PubMed

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記述言語：英語  

DOI： 10.1111/1346-8138.16866

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Psoriasis is a chronic skin disease with interleukin (IL)-17-dominated inflammation and hyperproliferation of epidermis. Dietary fiber is fermented by the gut microbiome into short-chain fatty acids (SCFAs) that manifest anti-inflammatory effects. We examined if feeding with an inulin-enriched high-fiber diet (HFD) might improve topical imiquimod-induced psoriasis-like dermatitis in mice. HFD reduced thickening and total severity scores of imiquimod-induced dermatitis and reduced epidermal thickness, inflammatory infiltrates, including Ly6G+ neutrophils, and epidermal Ki67+ proliferating cells. HFD reduced mRNA levels of IL-17A, IL-17F, IL-22, IL-1β, tumor necrosis factor (TNF)-α, CXCL1, CXCL2, and keratin 16 and increased those of transforming growth factor (TGF)-β1 and cyclin-dependent kinase inhibitor 1A in imiquimod-induced dermatitis. In 16S rRNA sequencing of the gut microbiome, imiquimod increased relative abundance of phylum Firmicutes, while HFD increased that of phylum Bacteroidota and genus Bacteroides. HFD increased serum and fecal concentrations of SCFA propionate. Oral propionate reduced inflammatory infiltrates and epidermal Ki67+ cells and reduced mRNA levels of IL-17A, IL-17F, IL-17C, IL-22, IL-1β, IL-6, TNF-α, CXCL1, CCL20 and increased those of TGF-β1and IL-10 in imiquimod-indued dermatitis. Dietary inulin supplementation improves imiquimod-induced psoriasis-like dermatitis partially via propionate, and may be a promising adjunctive therapy for psoriasis.

DOI： 10.3390/ijms241814197

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Atopic dermatitis (AD) is a chronic eczematous disease with various types of rash, erythema, edema/papulation, excoriation, or lichenification. Janus kinase 1 inhibitor upadacitinib is effective for moderate-to-severe AD. We aimed to investigate the therapeutic effects of upadacitinib on each rash type in AD patients in real-world clinical practice. Seventy-two Japanese patients with moderate-to-severe AD were treated with oral upadacitinib 15 mg/day plus topical corticosteroids. The Eczema Area and Severity Index (EASI) scores for erythema, edema/papulation, excoriation, or lichenification on the whole body or on head and neck, upper limbs, lower limbs, or trunk were assessed at weeks 0, 4, and 12 of treatment. The proportions of patients who achieved resolution or at least 75% reduction of EASI from baseline (EASI 75) for individual rash types were calculated at weeks 4 and 12 on the whole body or each anatomical site. The resolution rates for excoriation, erythema, edema/papulation, or lichenification on the whole body were 38.3%, 23.7%, 21.7%, and 8.3% at week 4 and 18.3%, 18.6%, 11.6%, and 13.3% at week 12, respectively. The EASI scores for all rash types significantly decreased at weeks 4 and 12 compared to week 0. The achievement rates of EASI 75 for excoriation, erythema, edema/papulation, or lichenification on the whole body were 67.2%, 66.7%, 49.2%, and 37.7% at week 4 and 57.3%, 65%, 41%, and 41% at week 12, respectively. The achievement rate of EASI 75 for erythema on head and neck at week 4 (45.3%) was lower than that on upper limbs (71%) and on lower limbs (70.8%), and that on head and neck at week 12 (42.2%) was lower than that on lower limbs (69.2%). These results indicate that upadacitinib is effective for all AD rash types, especially for excoriation and erythema, while head-and-neck erythema might be less responsive to upadacitinib.

DOI： 10.1111/1346-8138.16950

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Dietary habits may modulate the pathogenesis of BP. OBJECTIVES: We evaluated dietary habits in Japanese patients with BP and compared their results to those of age- and sex-matched healthy controls. We also examined the relationship between dietary habits versus IgG anti-BP180NC16A antibody or parameters of BP disease area index (BPDAI); cutaneous blisters/erosions, cutaneous urticaria/erythema, and mucosal blisters/erosions. MATERIALS & METHODS: Dietary habits were assessed by the validated, Brief-type self-administered Diet History Questionnaire. Severity of disease was assessed with BPDAI. RESULTS: Patients with BP showed a lower intake of retinol (vitamin A1) and beverages, and a higher intake of seasoning/spices, compared to controls. The bivariate and multivariable logistic regression analysis showed that BP was associated with a low intake of retinol and beverages. There were no significant correlations between IgG anti-BP180NC16A antibody levels and intake of nutrients/foods. The BPDAI score for cutaneous blisters/erosions significantly positively correlated with intake of carbohydrate and negatively with intake of retinol, vitamin A, animal fat, cholesterol, phosphorus, and vitamin B2. The BPDAI score for cutaneous urticaria/erythema significantly negatively correlated with intake of vitamin A. BP patients with mucosal blisters/erosions had a higher intake of cholesterol, n-6 polyunsaturated fatty acid, and eggs, and lower intake of seasoning/spices, compared to patients without BP. CONCLUSION: The supplementation of vitamin A might have prophylactic and/or therapeutic effects on BP.

DOI： 10.1684/ejd.2023.4527

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Upadacitinib, an oral Janus kinase 1 inhibitor approved for treating atopic dermatitis (AD), can cause adverse events such as herpes zoster (HZ) and acne. We aimed to identify background factors predicting the occurrence of HZ and acne during upadacitinib treatment in patients with AD. From August 2021 to December 2022, 112 Japanese patients with moderate-to-severe AD (aged ≥12 years) were treated with upadacitinib 15 mg/day (78 patients) or 30 mg/day (34 patients) plus topical corticosteroids or delgocitinib limited to head and neck for 3-9 months. AD patients with the occurrence of HZ during upadacitinib treatment had higher incidences for history of HZ and of bronchial asthma than those without in the upadacitinib 15 mg, 30 mg, and whole groups. AD patients with occurrence of HZ had higher pretreatment values of lactate dehydrogenase and eczema area and severity index on head and neck compared to those without in the upadacitinib 15 mg and whole groups. Logistic regression analysis revealed that history of HZ was associated with the occurrence of HZ in the upadacitinib 15 mg and whole groups. The proportion of underage patients (<18 years) was higher in patients with occurrence of acne compared to those without in the upadacitinib 30 mg group, but no significant differences were found in the other background factors between the two patient populations. History of HZ may predict the occurrence of HZ during upadacitinib treatment in patients with AD.

DOI： 10.1111/1346-8138.16879

PubMed

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The authors evaluated the efficacy and safety of baricitinib, a Janus kinase 1/2 inhibitor, for atopic dermatitis (AD) in real-world practice. From August 2021 to September 2022, 36 patients aged ≥15 years with moderate to severe AD were treated with oral baricitinib 4 mg/day plus topical corticosteroids. Baricitinib improved clinical indexes; the percent reduction at weeks 4 and 12 was a median of 69.19% and 69.98% for the Eczema Area and Severity Index (EASI), 84.52% and 76.33% for the Atopic Dermatitis Control Tool, and 76.39% and 64.58% for Peak Pruritus Numerical Rating Score, respectively. The achievement rate of EASI 75 was 38.89% and 33.33% at weeks 4 and 12, respectively. The percent reduction of EASI in the head and neck, upper limbs, lower limbs, and trunk was 56.9%, 68.3%, 80.7%, and 62.5% at week 12, respectively, with a significant difference between the head and neck versus the lower limbs. Baricitinib decreased thymus and activation-regulated chemokine, lactate dehydrogenase, and total eosinophil count at week 4. Baseline EASI of the head and neck negatively correlated with percent reduction of EASI at week 4, while baseline EASI of the lower limbs positively correlated with percent reduction of EASI at week 12. Treatment-emergent adverse events included elevation of creatine phosphokinase (11.1%), herpes labialis (5.6%), furuncle (8.3%), and exacerbation of AD (1%), without serious treatment-emergent adverse events. In this real-world study, baricitinib was well tolerated for patients with AD and achieved therapeutic effects comparable to those in clinical trials. High baseline EASI of the lower limbs might predict good treatment response at week 12, while high baseline EASI of the head and neck might predict poor treatment response at week 4 in baricitinib treatment for AD.

DOI： 10.1111/1346-8138.16763

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.16866

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Atopic dermatitis (AD) is a chronic inflammatory skin disease with severe itch. The eosinophil-to-lymphocyte ratio (ELR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) are reported to reflect itch or the severity of AD. We examined if these parameters may act as indicators for therapeutic effects of the Janus kinase 1 inhibitor upadacitinib for patients with AD in real-world clinical practice. Between August 2021 and September 2023, 65 Japanese patients (aged ≥ 12 years) with moderate to severe AD were treated with 15 mg/day of oral upadacitinib, plus twice daily topical corticosteroids. Before treatment, the baseline ELR, NLR, MLR, and PLR levels positively correlated with the eczema area and severity index (EASI), while the baseline NLR and PLR levels positively correlated with the peak pruritus-numerical rating scale (PP-NRS). After upadacitinib treatment, ELR and NLR remarkably decreased at week 4 and the reduced levels were maintained until week 24, in parallel with EASI and PP-NRS, while MLR and PLR transiently reduced at week 4, but returned to baseline levels after week 12. The percent reduction of ELR significantly correlated with the percent reductions of EASI and PP-NRS at weeks 4, 12, and 24 of upadacitinib treatment. ELR may act as an indicator for the improvement of clinical signs and itch by upadacitinib treatment in AD.

DOI： 10.3390/jcm12062201

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The authors evaluated the efficacy and safety of baricitinib, a Janus kinase 1/2 inhibitor, for atopic dermatitis (AD) in real-world practice. From August 2021 to September 2022, 36 patients aged ≥15 years with moderate to severe AD were treated with oral baricitinib 4 mg/day plus topical corticosteroids. Baricitinib improved clinical indexes; the percent reduction at weeks 4 and 12 was a median of 69.19% and 69.98% for the Eczema Area and Severity Index (EASI), 84.52% and 76.33% for the Atopic Dermatitis Control Tool, and 76.39% and 64.58% for Peak Pruritus Numerical Rating Score, respectively. The achievement rate of EASI 75 was 38.89% and 33.33% at weeks 4 and 12, respectively. The percent reduction of EASI in the head and neck, upper limbs, lower limbs, and trunk was 56.9%, 68.3%, 80.7%, and 62.5% at week 12, respectively, with a significant difference between the head and neck versus the lower limbs. Baricitinib decreased thymus and activation-regulated chemokine, lactate dehydrogenase, and total eosinophil count at week 4. Baseline EASI of the head and neck negatively correlated with percent reduction of EASI at week 4, while baseline EASI of the lower limbs positively correlated with percent reduction of EASI at week 12. Treatment-emergent adverse events included elevation of creatine phosphokinase (11.1%), herpes labialis (5.6%), furuncle (8.3%), and exacerbation of AD (1%), without serious treatment-emergent adverse events. In this real-world study, baricitinib was well tolerated for patients with AD and achieved therapeutic effects comparable to those in clinical trials. High baseline EASI of the lower limbs might predict good treatment response at week 12, while high baseline EASI of the head and neck might predict poor treatment response at week 4 in baricitinib treatment for AD.

DOI： 10.1111/1346-8138.16763

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Psoriasis is associated with cardiometabolic and cardiovascular diseases. Biologic therapy targeting tumor necrosis factor (TNF)-α, interleukin (IL)-23, and IL-17 may improve not only psoriasis but also cardiometabolic diseases. We retrospectively evaluated whether biologic therapy improved various indicators of cardiometabolic disease. Between January 2010 and September 2022, 165 patients with psoriasis were treated with biologics targeting TNF-α, IL-17, or IL-23. The patients' body mass index; serum levels of HbA1c, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol, triglyceride (TG), and uric acid (UA); and systolic and diastolic blood pressures were recorded at weeks 0, 12, and 52 of the treatment. Baseline psoriasis area and severity index (week 0) positively correlated with TG and UA levels but negatively correlated with HDL-C levels, which increased at week 12 of IFX treatment compared to those at week 0. UA levels decreased at week 12 after ADA treatment compared with week 0. HDL-C levels decreased 52 weeks after IXE treatment. In patients treated with TNF-α inhibitors, HDL-C levels increased at week 12, and UA levels decreased at week 52, compared to week 0. Thus, the results at two different time points (at weeks 12 and 52) were inconsistent. However, the results still indicated that TNF-α inhibitors may improve hyperuricemia and dyslipidemia.

DOI： 10.3390/jcm12051934

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We performed a retrospective and observational study of patients with psoriasis. The aim of this study was to define the laboratory indicators reflecting the treatment response to tumor necrosis factor (TNF)-α inhibitors and the predictors for the treatment response. From January 2010 to June 2022, 28, 15 and 12 patients with psoriasis were treated with infliximab (IFX), adalimumab (ADA) and certolizumab pegol (CZP), respectively. The values of C-reactive protein (CRP), platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio and monocyte to lymphocyte ratio decreased in parallel with psoriasis area and severity index (PASI) at weeks 12 and 52 of treatment. The percentage reduction of the CRP was correlated with that of the PASI at week 52 in all patients and subgroups treated with IFX. The percentage reduction of the PLR was correlated with that of the PASI at week 52 in all patients. Linear multivariate regression analyses revealed that the presence of scalp lesions was associated with a high percentage reduction of the PASI at week 52 in the ADA subgroup. The CRP and PLR might act as biomarkers reflecting the treatment response to TNF-α inhibitors in patients with psoriasis. The presence of scalp lesions might be a predictive factor for a high treatment response to ADA in patients with psoriasis.

DOI： 10.3390/jcm12030974

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The status of dupilumab self-injection at home is not well understood. We therefore aimed to identify the barriers to adherence to dupilumab self-injection. PATIENTS AND METHODS: This non-interventional open-label study was conducted between March 2021 and July 2021. Patients with atopic dermatitis, bronchial asthma, and chronic rhinosinusitis with nasal polyps receiving dupilumab, from 15 sites, were requested to complete a self-administered questionnaire regarding the frequency and effectiveness of dosing as well as their use and satisfaction with dupilumab. Barriers to adherence were assessed using the Adherence Starts with Knowledge-12. RESULTS: We included 331 patients who used dupilumab for atopic dermatitis (n = 164), chronic rhinosinusitis with nasal polyps (n = 102), and bronchial asthma (n = 65). The median efficacy of dupilumab scored 9.3 on the visual analog scale. Overall, 85.5% of the patients self-injected dupilumab, and 70.7% perfectly complied with the established injection dates. The pre-filled pen was significantly superior to the conventional syringe in terms of usability, operability, ease of pushing the plunger, and patient satisfaction. However, the pre-filled pen caused more pain during self-injection than did the syringe. Multivariate logistic regression analysis showed that adherence decreased with longer dupilumab treatment duration (p = 0.017) and was not associated with age, sex, underlying disease, or device type. There was a difference in responses related to "inconvenience/forgetfulness" between the good and poor adherence groups. CONCLUSION: The pre-filled dupilumab pen was superior to the syringe in terms of usability, operability, ease of pushing the plunger, and satisfaction. Repetitive instructions are recommended for preventing poor adherence to dupilumab self-injection.

DOI： 10.2147/PPA.S389865

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We previously analyzed data from blood examination screenings, including serum Krebs von den Lungen (KL) -6 level, before starting biologic treatment for psoriasis in a real-world setting. However, we did not follow change in KL-6 level after the initiation of biologics. Furthermore, there has been no follow-up study of certolizumab pegol, risankizumab, or tildrakizumab. This study evaluated change in serum KL-6 levels in patients during treatment with biologics, including certolizumab pegol, risankizumab, and tildrakizumab. METHODS: We analyzed data from 111 patients. Change in KL-6 level was regarded as significant if it increased to greater than 500 U/mL at least once and if the maximum level after treatment with biologics was at least 1.5 times that of the baseline level. RESULTS: KL-6 level significantly changed during treatment with TNF inhibitors, IL-17 inhibitors, and IL-23 inhibitors in 9 (20.9%), 2 (6.3%), and 2 (5.6%) patients, respectively. Mean age, mean baseline KL-6 level, and frequency of TNF inhibitor use were higher in patients with a significant change in KL-6 level than those in patients without a significant change. Ten patients had minor interstitial changes on chest CT scans but no clinical signs suggesting interstitial pneumonia. CONCLUSIONS: Older patients with psoriasis and high baseline KL-6 levels must be carefully monitored during treatment with biologics, especially TNF inhibitors. Monitoring of KL-6 level and chest CT scans is necessary to exclude the possibility of drug-induced interstitial pneumonia.

DOI： 10.1272/jnms.JNMS.2023_90-207

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We previously evaluated blood screening data, including antinuclear antibodies (ANA), before initiating biologic treatment for patients with psoriasis in a real-world setting. However, we did not analyze change in ANA titers after the start of biologics. No previous study has comprehensively investigated change in ANA titers over time in individual patients or the effectiveness of certolizumab pegol or tildrakizumab. OBJECTIVES: This study evaluated change in ANA titers in individual patients during treatment with biologics, including certolizumab pegol and tildrakizumab. METHODS: 111 patients were included in this study. Change in ANA was regarded as significant when the ANA titer was ×80 or more in patients with a previously undetectable ANA titer or when it increased by fourfold or more in those with a detectable ANA titer before treatment. RESULTS: The ratios of patients with a significant change in ANA titer who were treated with a tumor necrosis factor (TNF) inhibitor, interleukin (IL) -17 inhibitor, or IL-23 inhibitor were 34.9% (15/43), 0.0% (0/32), and 0.0% (0/36), respectively. There were 4 patterns of significant change in ANA titer: (i) an increase (n=8), (ii) a decrease after an increase (n=4), (iii) a decrease after an increase with a drug change (n=2), and (iv) an increase after a decrease after an increase (n=1). No symptom suggesting lupus syndrome was noted. CONCLUSIONS: ANA titers must be carefully monitored throughout treatment with biologics, especially TNF inhibitors, and the possibility of lupus-like syndrome should be excluded.

DOI： 10.1272/jnms.JNMS.2023_90-115

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: To investigate the therapeutic effectiveness and safety of Janus kinase 1 inhibitor upadacitinib in adolescent patients with atopic dermatitis (AD). PATIENTS AND METHODS: This study examined therapeutic effectiveness and safety of upadacitinib for 39 Japanese adolescent patients (aged 12-17 years) diagnosed with moderate-to-severe AD from August 2021 to January 2023. The patients were treated with upadacitinib 15 mg/day plus twice daily topical corticosteroids. Total eczema area and severity index (EASI) or EASI on head and neck, upper limbs, lower limbs, and trunk or for erythema, edema/papulation, excoriation, or lichenification, atopic dermatitis control tool (ADCT), peak pruritus-numerical rating scale (PP-NRS), and laboratory indexes were assessed at weeks 0, 4, and 12 of treatment. Treatment-emergent adverse events were recorded. RESULTS: Total EASI or EASI on 4 anatomical sites or for 4 rash types, ADCT, and PP-NRS were significantly reduced at week 4 and 12 compared to week 0. The achievement rates at weeks 4 or 12 were 64.1% or 62.5% for EASI 75, 93.5% or 73.1% for ADCT <7-point, and 80.6% or 60% for PP-NRS ≥4-point improvement, respectively, indicating their peak at week 4 and slight decrease at week 12. The percent reduction of EASI for excoriation was higher than that for lichenification or edema/papulation at week 4 or week 12, respectively. The percent reductions of EASI for erythema and edema/papulation on head and neck were lower than those on lower limbs at week 12. Total eosinophil counts (TEC) and IgE reduced at week 4 compared to week 0 while TARC, IgE, TEC, and LDH increased at week 12 compared to week 4. CONCLUSION: These results suggest therapeutic effectiveness and tolerability of upadacitinib and support its therapeutic usefulness for adolescent AD patients.

DOI： 10.2147/CCID.S439053

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tumor necrosis factor (TNF) inhibitors, including adalimumab, are widely used to treat refractory psoriatic arthritis (PsA). Although isoniazid chemoprophylaxis is generally effective in preventing reactivation of latent tuberculosis infection (LTBI), prophylactic measures do not fully protect against development of active tuberculosis. We report a rare case of active tuberculosis despite chemoprophylaxis for LTBI in a patient receiving adalimumab for PsA. A 60-year-old Japanese woman who had received a diagnosis of psoriasis at age 35 years presented with arthralgia of the right hand, which she first noticed 2 months previously. Physical examination showed scattered erythematous papules and plaques with scales on her trunk, extremities, and scalp. Her right metacarpophalangeal and proximal interphalangeal joints were swollen and painful, and her right wrist and elbow were painful. PsA was diagnosed and adalimumab was initiated. Because an interferon-γ release assay (IGRA) showed a borderline result at screening, isoniazid was administered as chemoprophylaxis for LTBI. At 22 months after initiation of adalimumab, IGRA was positive and chest CT disclosed centrilobular nodules in both lungs and swelling of multiple lymph nodes. Culture of sputum at 24 months demonstrated Mycobacterium tuberculosis. Active tuberculosis was diagnosed, and treatment with a combination of isoniazid, rifampicin, ethambutol hydrochloride, and pyrazinamide was started. To ensure timely diagnosis and treatment of active tuberculosis, a tuberculosis expert should be consulted at an early stage, with regular screening and monitoring.

DOI： 10.1272/jnms.JNMS.2023_90-610

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We evaluated the efficacy and safety of upadacitinib, janus kinase 1 inhibitor for atopic dermatitis (AD) in real-world practice. From September 2021 to March 2022, 31 patients with moderate-to-severe AD, aged ≥12 years were treated with oral upadacitinib 15 mg/day plus topical corticosteroids. Upadacitinib reduced clinical indexes compared to baseline levels: percent reduction at week 4 and 12 (median) was 73.6% and 85.6% in eczema area and severity index (EASI); 81.3% and 81.3% in AD control tool (ADCT); and 70% and 75% in peak pruritus numerical rating score (PP-NRS), respectively. The achievement rate of EASI 75 was 51.6% and 67.7% at week 4 and 12, respectively. Upadacitinib reduced serum lactate dehydrogenase and total eosinophil count (TEC) at week 4 and 12, and thymus and activation-regulated chemokine and immunoglobulin E at week 4, compared to baseline levels. Percent reduction of TEC was correlated with that of EASI at week 4 and 12. Baseline TEC was positively correlated with the percent reduction of EASI at week 4. Percent reduction of EASI in female patients was higher than that in male patients at week 4 and 12. Linear multivariate regression analyses revealed that high percent reduction of EASI at week 4 or 12 was associated with high baseline TEC or female gender, respectively. There were no serious treatment-emergent adverse events. Adverse events include acne (5%), elevation of creatine phosphokinase (9.7%), herpes zoster (1%), and AD (1%). Upadacitinib plus topical corticosteroids for patients with AD in the real-world practice was well tolerated and gave therapeutic effects comparable with those in previous clinical trials. The ADCT and PP-NRS rapidly reduced at week 4 while EASI gradually reduced until week 12. The TEC might act both as a predictive factor of response at week 4 and as a biomarker reflecting therapeutic effects in upadacitinib treatment for AD.

DOI： 10.1111/1346-8138.16549

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記述言語：英語  

The pathomechanisms of various skin diseases have recently been elucidated progressively [...].

DOI： 10.3390/ijms232012396

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Among human cutaneous malignancies, basal cell carcinoma is the most common. Solid advances in unveiling the molecular mechanisms of basal cell carcinoma have emerged in recent years. In Gorlin syndrome, which shows basal cell carcinoma predisposition, identification of the patched 1 gene (PTCH1) mutation was a dramatic breakthrough in understanding the carcinogenesis of basal cell carcinoma. PTCH1 plays a role in the hedgehog pathway, and dysregulations of this pathway are known to be crucial for the carcinogenesis of many types of cancers including sporadic as well as hereditary basal cell carcinoma. In this review, we summarize the clinical features, pathological features and hedgehog pathway as applied in basal cell carcinoma. Other crucial molecules, such as p53 and melanocortin-1 receptor are also discussed. Due to recent advances, therapeutic strategies based on the precise molecular mechanisms of basal cell carcinoma are emerging. Target therapies and biomarkers are also discussed.

DOI： 10.3390/ijms231911968

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We evaluated the efficacy and safety of upadacitinib, janus kinase 1 inhibitor for atopic dermatitis (AD) in real-world practice. From September 2021 to March 2022, 31 patients with moderate-to-severe AD, aged ≥12 years were treated with oral upadacitinib 15 mg/day plus topical corticosteroids. Upadacitinib reduced clinical indexes compared to baseline levels: percent reduction at week 4 and 12 (median) was 73.6% and 85.6% in eczema area and severity index (EASI); 81.3% and 81.3% in AD control tool (ADCT); and 70% and 75% in peak pruritus numerical rating score (PP-NRS), respectively. The achievement rate of EASI 75 was 51.6% and 67.7% at week 4 and 12, respectively. Upadacitinib reduced serum lactate dehydrogenase and total eosinophil count (TEC) at week 4 and 12, and thymus and activation-regulated chemokine and immunoglobulin E at week 4, compared to baseline levels. Percent reduction of TEC was correlated with that of EASI at week 4 and 12. Baseline TEC was positively correlated with the percent reduction of EASI at week 4. Percent reduction of EASI in female patients was higher than that in male patients at week 4 and 12. Linear multivariate regression analyses revealed that high percent reduction of EASI at week 4 or 12 was associated with high baseline TEC or female gender, respectively. There were no serious treatment-emergent adverse events. Adverse events include acne (5%), elevation of creatine phosphokinase (9.7%), herpes zoster (1%), and AD (1%). Upadacitinib plus topical corticosteroids for patients with AD in the real-world practice was well tolerated and gave therapeutic effects comparable with those in previous clinical trials. The ADCT and PP-NRS rapidly reduced at week 4 while EASI gradually reduced until week 12. The TEC might act both as a predictive factor of response at week 4 and as a biomarker reflecting therapeutic effects in upadacitinib treatment for AD.

DOI： 10.1111/1346-8138.16549

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hailey-Hailey disease (HHD) is an autosomal dominant genodermatosis and the defective gene in HHD is ATP2C1, which encodes secretory pathway Ca2+ /Mn2+ ATPase type 1 (SPCA1). Here we report four Japanese HHD patients showing three kinds of mutations with premature termination codons in the ATP2C1 gene, including two novel ones. Patient 1 was a 39-year-old man with a novel heterozygous mutation, c.664dup in exon 8 (p.N215Kfs*26). Patient 2 was a 33-year-old man (the younger brother of patient 1) with the same mutation as patient 1. Patient 3 was a 55-year-old man with a previously reported heterozygous mutation, c.519dup in exon 7 (p.R174Tfs*4). Patient 4 was a 33-year-old woman with a novel heterozygous mutation, c.2640del in exon 27 (p.L881Ffs*10). The clinical characteristics of our four cases varied in disease severity and the response to treatment. The present cases enrich the database of mutational analysis for HHD.

DOI： 10.1111/1346-8138.16353

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本形成外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本形成外科学会  

2015年1月〜2020年12月に当科で経験した脂腺母斑(疑い)症例36例の統計学的検討を行った。その結果、受診時年齢は0〜10歳が最も多く17例で、11〜40歳が10例、41歳以降が9例であった。脂腺母斑上に新たな腫瘍が生じた症例は6例(16.7%)であり、年齢はすべて41歳以降の症例で、男性4例、女性2例であった。合併腫瘍の部位は頭頂部が3例と最多で、次いで左後頭部、後頭部、左側頭部〜左耳前部が各1例であった。合併腫瘍の病理診断は毛芽腫が3例、有棘細胞癌、乳頭状汗管嚢胞腺癌、毛芽腫・基底細胞癌・脂腺腫が各3例であった。

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by hyperproliferation of epidermal keratinocytes. Biologics have been available for the treatment of patients with refractory psoriasis since 2010 in Japan, and as of December 2021, 10 biologics were available. The Biologics Review Committee of the Japanese Dermatological Association for Psoriasis recommends blood examination tests for antinuclear antibodies (ANA), Krebs von den Lugen (KL)-6, hepatitis B surface antigen (HBsAg), hepatitis B surface antibodies (HBsAb), hepatitis B core antibodies (HBcAb), hepatitis C virus (HCV) antibodies, HIV antibodies, human T-cell leukemia virus (HTLV)-1 antibodies, β-D-glucan, and the T-cell spot (T-SPOT) test before initiation of biologics at screening. In this study, we evaluated the use of biologics for 127 psoriasis patients and the blood examination screening data before initiation of biologics in the real-world setting. Tumor necrosis factor inhibitors, interleukin (IL)-17 inhibitors and IL-23 inhibitors were initiated for 54 (42.5%), 36 (28.3%), and 37 (29.1%) patients, respectively. The numbers of patients positive for ANA, HBsAg, HBsAb, HBcAb, HCV antibody, HIV antibody, HTLV-1 antibody, and T-SPOT were 27 (21.3%), 0 (0%), 22 (17.3%), 20 (15.7%), three (2.4%), zero (0%), one (0.8%), and 4 (3.1%), respectively. The numbers of patients whose KL-6 and β-D-glucan levels were higher than the reference values were seven (5.5%) and seven (5.5%), respectively. In the real-world setting, it is sometimes unavoidable to use biologics for those patients with abnormal data although careful monitoring is necessary.

DOI： 10.1111/1346-8138.16333

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by hyperproliferation of epidermal keratinocytes. Biologics have been available for the treatment of patients with refractory psoriasis since 2010 in Japan, and as of December 2021, 10 biologics were available. The Biologics Review Committee of the Japanese Dermatological Association for Psoriasis recommends blood examination tests for antinuclear antibodies (ANA), Krebs von den Lugen (KL)-6, hepatitis B surface antigen (HBsAg), hepatitis B surface antibodies (HBsAb), hepatitis B core antibodies (HBcAb), hepatitis C virus (HCV) antibodies, HIV antibodies, human T-cell leukemia virus (HTLV)-1 antibodies, β-D-glucan, and the T-cell spot (T-SPOT) test before initiation of biologics at screening. In this study, we evaluated the use of biologics for 127 psoriasis patients and the blood examination screening data before initiation of biologics in the real-world setting. Tumor necrosis factor inhibitors, interleukin (IL)-17 inhibitors and IL-23 inhibitors were initiated for 54 (42.5%), 36 (28.3%), and 37 (29.1%) patients, respectively. The numbers of patients positive for ANA, HBsAg, HBsAb, HBcAb, HCV antibody, HIV antibody, HTLV-1 antibody, and T-SPOT were 27 (21.3%), 0 (0%), 22 (17.3%), 20 (15.7%), three (2.4%), zero (0%), one (0.8%), and 4 (3.1%), respectively. The numbers of patients whose KL-6 and β-D-glucan levels were higher than the reference values were seven (5.5%) and seven (5.5%), respectively. In the real-world setting, it is sometimes unavoidable to use biologics for those patients with abnormal data although careful monitoring is necessary.

DOI： 10.1111/1346-8138.16333

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Three categories of biologics-tumor necrosis factor (TNF) inhibitors, interleukin (IL) -17 inhibitors, and IL-23 inhibitors-are available for treatment of refractory psoriasis. Recent studies have shown that laboratory biomarkers such as peripheral blood neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and serum C-reactive protein (CRP) levels are associated with psoriasis or its severity. This study evaluated associations of transition of NLR, PLR, MLR, and CRP with transition of disease activity in psoriasis patients treated with the three categories of biologics. METHODS: Data from 67 patients were analyzed. Associations of transition of psoriasis area and severity index (PASI) score with the abovementioned laboratory markers were evaluated by using a mixed effects model with PASI as the response variable, laboratory markers as fixed effects collectively, and patients as random effects. RESULTS: In an analysis of all the patients, serum CRP and NLR were associated with PASI score (P=0.006 and P=0.001, respectively). In patients treated with TNF inhibitors, CRP and NLR were associated with PASI score (P=0.043 and P=0.002, respectively). In patients treated with IL-17 inhibitors, NLR was associated with PASI score (P=0.001). CONCLUSIONS: NLR appears to be the most reliable biomarker of the effect of treatment with biologics, especially IL-17 inhibitors.

DOI： 10.1272/jnms.JNMS.2022_89-613

PubMed

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Darier's disease (DD) is a rare autosomal dominant genodermatosis caused by mutations in the ATP2A2 gene, which encodes for the sarcoendoplasmic reticulum calcium ATPase type 2 isoform (SERCA2). In epidermal keratinocytes, the decrease in SERCA2 inhibits the transportation of desmosomal proteins to the plasma membrane, resulting in acantholysis and dyskeratosis. We present the first case of DD with a novel missense mutation in the ATP2A2 gene and successfully treated with calcipotriol/betamethasone dipropionate two-compound ointment. A 34-year-old Japanese woman presented with erythema and scales on the scalp and clusters of keratotic papules on the neck and groin. Similar symptoms were observed in her father, younger sister, and daughter. Histopathological examination revealed corps ronds in the granular layer and grains in the horny layer of the epidermis and acantholytic lacuna just above the basal layer. She was diagnosed with DD. A novel heterozygous missense mutation, c.616A>C (p.Asn206His), was detected in the ATP2A2 gene in both the patient and her daughter. The patient was treated with calcipotriol/betamethasone dipropionate two-compound ointment, which resulted in improvement of the skin eruption. This two-compound topical ointment may be a promising therapeutic strategy in the treatment for DD.

DOI： 10.2147/CCID.S354694

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5021/ad.2021.33.6.593

PubMed

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版(株)  

＜文献概要＞51歳,女性。X年8月,口腔内,両眼球の乾燥が出現した。X+1年3月に唾液腺シンチグラフィで唾液の,シルマー試験で涙液の分泌低下が検出され,抗SS-A抗体および抗SS-B抗体陽性で,当院耳鼻咽喉科にてSjoegren症候群と診断された。X+2年12月,前頭部に脱毛を伴う紅斑が出現し,皮膚生検で真皮網状層のムチン沈着を認め,lupus erythematosus tumidusと診断した。X+3年3月,当科にてヒドロキシクロロキン硫酸塩200mg/日と400mg/日を隔日で内服開始し,同年5月には脱毛が軽減し,7月には紅斑も消退した。自験例はSjoegren症候群にlupus erythematosus tumidusを合併した2例目の報告例である。Lupus erythematosus tumidusの発症とSjoegren症候群あるいは抗SS-A抗体との関連については,今後の症例の蓄積と基礎研究による解明が望まれる。

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks signalling pathways of interleukin (IL)-4 and IL-13, is effective in treating patients with atopic dermatitis (AD). We previously showed that transitions of serum thymus and activation-regulated chemokine (TARC) levels and eosinophil numbers were strongly associated with that of AD activity and that the transitions of serum lactate dehydrogenase (LDH) and immunoglobulin E (IgE) levels were weakly and not associated with that of AD activity, respectively, in patients treated without dupilumab. OBJECTIVES: The purpose of this study was to elucidate whether the association of the transition of laboratory marker levels and transition of disease activity in dupilumab-treated AD patients (present study) was different from that in patients who are not treated with dupilumab (previous study). METHODS: Sixty AD outpatients treated with dupilumab were included in this study. Associations between the transition of the eczema area and severity index (EASI) score and those of above-mentioned laboratory marker levels were evaluated using a mixed effects model of EASI as the response variable, laboratory markers as fixed effects and patients as random effects. RESULTS: The transitions of serum TARC and LDH levels were associated strongly with that of AD activity, but the transitions of serum IgE level and eosinophil numbers were associated with that of AD activity intermediately and weakly, respectively. CONCLUSIONS: Laboratory markers are useful for evaluating the effects of treatments for AD, but the meaning of each laboratory marker depends on the drugs used for treatment.

DOI： 10.1111/ajd.13719

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks signalling pathways of interleukin (IL)-4 and IL-13, is effective in treating patients with atopic dermatitis (AD). We previously showed that transitions of serum thymus and activation-regulated chemokine (TARC) levels and eosinophil numbers were strongly associated with that of AD activity and that the transitions of serum lactate dehydrogenase (LDH) and immunoglobulin E (IgE) levels were weakly and not associated with that of AD activity, respectively, in patients treated without dupilumab. OBJECTIVES: The purpose of this study was to elucidate whether the association of the transition of laboratory marker levels and transition of disease activity in dupilumab-treated AD patients (present study) was different from that in patients who are not treated with dupilumab (previous study). METHODS: Sixty AD outpatients treated with dupilumab were included in this study. Associations between the transition of the eczema area and severity index (EASI) score and those of above-mentioned laboratory marker levels were evaluated using a mixed effects model of EASI as the response variable, laboratory markers as fixed effects and patients as random effects. RESULTS: The transitions of serum TARC and LDH levels were associated strongly with that of AD activity, but the transitions of serum IgE level and eosinophil numbers were associated with that of AD activity intermediately and weakly, respectively. CONCLUSIONS: Laboratory markers are useful for evaluating the effects of treatments for AD, but the meaning of each laboratory marker depends on the drugs used for treatment.

DOI： 10.1111/ajd.13719

PubMed

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記述言語：英語  

DOI： 10.1111/1346-8138.15974

PubMed

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記述言語：英語  

DOI： 10.1111/1346-8138.16023

PubMed

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語  

DOI： 10.1111/1346-8138.16023

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.15974

PubMed

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担当区分：最終著者   記述言語：日本語   出版者・発行元：(株)協和企画  

＜文献概要＞症例のポイント ・28歳,妊娠6週の女性に生じたSweet病を経験した.・熱発,膝関節痛,倦怠感,口腔内アフタ性潰瘍により摂食困難となったが,入院安静で軽快した.・退院後の妊娠経過は正常であった.

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Herpes zoster (HZ) is caused by reactivation of latent varicella zoster virus (VZV) in the cranial nerve or dorsal root ganglia, with spread of the virus along the sensory nerve to the dermatome. Postherpetic neuralgia is a feared complication of HZ and impairs patients' quality of life enormously. However, there is no predictor of the duration of neuralgia. Our objective was to investigate whether there are correlations between the duration of neuralgia and serum levels of potential biomarkers in order to find practical predictors of the duration of neuralgia. Patients who were diagnosed with HZ at our hospital from April 2013 to January 2014 were included in this study. Serum levels of cytokines and other biomarkers were measured using commercial enzyme-linked immunosorbent assay kits. Thirty patients (15 men and 15 women) with HZ were enrolled in this study. The mean age was 66.1 ± 9.2 (standard deviation) years (range, 51-84 years). Four patients were evaluated as having mild, 19 as having moderate, and seven as having severe HZ. Patients with severe HZ suffered from neuralgia for a significantly longer period of time than patients with mild-to-moderate HZ (9.86 ± 8.25 months vs. 2.01 ± 2.68 months, severe vs. mild-to-moderate, p = 0.0021). The serum interleukin (IL)-10 level was significantly higher in patients with severe HZ than in those with mild-to-moderate HZ (12.93 ± 3.27 pg/mL vs. 6.74 ± 3.72 pg/mL; severe vs. mild-to-moderate; p = 0.0487). Furthermore, the serum IL-10 level was significantly correlated with the duration of neuralgia (r = 0.5193, p = 0.0111). Lastly, the serum IL-10 level significantly decreased after treatment in comparison with that before treatment (from 8.15 ± 4.46 pg/mL to 4.32 ± 11.83 pg/mL, p < 0.0001). In conclusion, these results suggest that the serum IL-10 level is an objective biomarker of the severity of HZ, and that the serum IL-10 level can be a practical predictor of the duration of neuralgia.

DOI： 10.1111/1346-8138.15818

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担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版(株)  

＜文献概要＞45歳,男性。初診時,左後頭部の,生下時よりある黄赤色小結節の癒合した局面上に,長径2.5cm大のドーム状に隆起し,びらんと痂皮を伴う淡紅色腫瘤を認めた。病理組織像では,表皮内に外方向性に突出する腫瘍細胞の胞巣を認め,腫瘍胞巣は腺管あるいは乳頭腫構造を呈し,真皮まで浸潤していた。腫瘍細胞は断頭分泌を伴う円柱上皮細胞と小型立方形細胞から構成され,核異型性を示した。腫瘍の下床には,毛包脂腺組織とアポクリン腺が増殖していた。脂腺母斑上に生じたsyringocystadenocarcinoma papilliferumと診断した。Syringocystadenocarcinoma papilliferumは極めてまれであるため,臨床・病理組織学的所見,治療法は確立しておらず,今後,症例の蓄積による検討が望まれる。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01266&link_issn=&doc_id=20210422110018&doc_link_id=10.18888%2Fhi.0000002488&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000002488&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Psoriasis is a chronic inflammatory skin disease characterized by IL-17-dominant abnormal innate and acquired immunity, and the hyperproliferation and aberrant differentiation of epidermal keratinocytes, and comorbid arthritis or cardiometabolic diseases. This Special Issue presented updated information on pathogenesis, comorbidities, and therapy of psoriasis. The pathogenesis of psoriasis may involve the dysfunction of indoleamine 2,3-dioxygenase 2 or of UBA domain containing 1-mediated regulation of CARD14/CARMA2sh. The blood cells of psoriasis patients showed the enhanced oxidative stress/autophagy flux and decreased 20S proteasome activity. Elafin, clusterin, or selenoprotein P may act as biomarkers for psoriasis and comorbid metabolic diseases. The proteomic profile of psoriasis lesions showed the dysfunction of dermal fibroblasts; up-regulation of proinflammatory factors and signal transduction or down-regulation of structural molecules. The skin inflammation in psoriasis may populate certain gut bacteria, such as Staphylococcus aureus and Streptococcus danieliae, which worsen the skin inflammation in turn. The psoriasis-associated pruritus may be caused by immune, nervous, or vascular mechanisms. In addition to current oral treatments and biologics, a new treatment option for psoriasis is now being developed, such as retinoic-acid-receptor-related orphan nuclear receptor γt inhibitors, IL-36 receptor antagonist, or aryl hydrocarbon receptor agonist. Antimicrobial peptides and innate immune cells, involved in the pathogenesis of psoriasis, may be novel therapeutic targets. The pathomechanisms and responses to drugs in collagen diseases are partially shared with and partially different from those in psoriasis. Certain nutrients can exacerbate or regulate the progress of psoriasis. The articles in this Special Issue will encourage attractive approaches to psoriasis by future researchers.

DOI： 10.3390/ijms22062979

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記述言語：英語  

DOI： 10.1111/1346-8138.15691

PubMed

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担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版(株)  

＜文献概要＞65歳,男性。初診時,咽頭・喉頭に多数のびらんがあり,左上腕と上背部に小紅斑が散在していた。背部紅斑の病理組織像は表皮下水疱,水疱内と真皮血管周囲のリンパ球,組織球,好酸球の浸潤を呈した。蛍光抗体直接法では表皮真皮境界部にIgG,C3が沈着し,蛍光抗体間接法は患者血清のIgGがsplit skinの表皮側に反応した。免疫ブロット法では患者血清のIgGがBP180のC末端,NC16a,120kDa LAD-1に反応した。抗BP180型粘膜類天疱瘡と診断した。ステロイド全身投与のみで症状は改善せず,血漿交換,免疫グロブリン大量静注療法で改善したが,ステロイド減量に伴い再燃し,ミゾリビン追加により症状は改善した。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01266&link_issn=&doc_id=20210126100011&doc_link_id=10.18888%2Fhi.0000002341&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000002341&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版(株)  

＜文献概要＞65歳,女性。背部,乳房下,臍部,頭皮に紅斑と少数の水疱,上下の歯肉にびらん,硬口蓋に血疱が出現した。組織学的に表皮下水疱を呈し,蛍光抗体直接法で表皮基底膜部にIgG,C3cの線状沈着を認め,1M食塩水剥離皮膚を基質とした蛍光抗体間接法で患者血清IgGが表皮側に反応した。免疫ブロット法ではBP180 NC16aとC末端部の組み換え蛋白に対するIgG抗体が検出された。抗BP180型粘膜類天疱瘡と診断。ミノサイクリン塩酸塩,ニコチン酸アミド内服で皮疹,口腔内病変は軽快した。抗BP180 NC16a抗体と抗C末端抗体陽性のMMP患者では,主として前者が皮疹の発症に,後者が粘膜病変の発症に寄与していると考える。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01266&link_issn=&doc_id=20210126100012&doc_link_id=10.18888%2Fhi.0000002342&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000002342&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版(株)  

＜文献概要＞7歳,女児。躯幹・四肢にそう痒を伴う紅斑,丘疹,痂皮が出現した。膿痂疹性湿疹を疑い,ステロイド外用や内服で治療するも難治性で,1年後に緊満性水疱が出現した。病理組織学的に好中球浸潤を伴う表皮下水疱を呈し,蛍光抗体直接法で基底膜にIgAの線状沈着を認め,1M食塩水剥離皮膚を用いた蛍光抗体間接法で,基底膜表皮側にIgAが陽性であった。小児型linear IgA bullous dermatosis lamina lucida typeと診断した。ジアミノジフェニルスルホン内服で皮疹は消退した。難治性で,そう痒を伴う蕁麻疹様紅斑を診た際には自己免疫性水疱症を考え,病理組織学的検査,蛍光抗体法などの検査を行う必要がある。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01266&link_issn=&doc_id=20210126100015&doc_link_id=10.18888%2Fhi.0000002345&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000002345&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版(株)  

＜文献概要＞65歳,男性。初診時,咽頭・喉頭に多数のびらんがあり,左上腕と上背部に小紅斑が散在していた。背部紅斑の病理組織像は表皮下水疱,水疱内と真皮血管周囲のリンパ球,組織球,好酸球の浸潤を呈した。蛍光抗体直接法では表皮真皮境界部にIgG,C3が沈着し,蛍光抗体間接法は患者血清のIgGがsplit skinの表皮側に反応した。免疫ブロット法では患者血清のIgGがBP180のC末端,NC16a,120kDa LAD-1に反応した。抗BP180型粘膜類天疱瘡と診断した。ステロイド全身投与のみで症状は改善せず,血漿交換,免疫グロブリン大量静注療法で改善したが,ステロイド減量に伴い再燃し,ミゾリビン追加により症状は改善した。

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記述言語：英語  

DOI： 10.1111/1346-8138.15622

PubMed

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Alopecia areata (AA) is characterized by non-scarring, patchy hair loss caused by autoimmune reactions to anagen hair follicles. The pathogenesis of AA may be affected by the diet. However, the dietary habits of patients with AA have not been precisely examined. Therefore, the aim of this study was to investigate the dietary habits of patients with AA in comparison to those of healthy controls. PATIENTS AND METHODS: We evaluated the dietary habits of 70 adult Japanese patients with AA using a brief-type self-administered diet history questionnaire and compared them to the habits of age- and sex-matched healthy controls. RESULTS: Japanese patients with AA had a higher body mass index (BMI) and higher intakes of vitamin C and fruit than the controls. Logistic regression analysis showed that AA was associated with BMI. Retinol intake was positively correlated with severity of alopecia tool (SALT) score, and linear regression analysis revealed that retinol intake was a predictor of SALT score. Retinol intake among patients with moderate to severe AA (ie, a SALT score >25) was higher than that in patients with mild AA (a SALT score ≤25). The mean age of AA patients with atopic dermatitis (AD) was lower than that of AA patients without AD; however, there were no differences in nutrient or food intake between these two groups. Logistic regression analysis showed that the comorbidity AD was negatively associated with age. CONCLUSION: AA was associated with a high BMI, and high retinol intake was a predictor of SALT score. Further studies should be conducted to clarify whether dietary intervention to reduce BMI or limit retinol intake can alter the development or severity of AA.

DOI： 10.2147/CCID.S335440

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Korean Dermatological Association and The Korean Society for Investigative Dermatology  

DOI： 10.5021/ad.2021.33.6.593

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その他リンク： https://anndermatol.org/DOIx.php?id=10.5021/ad.2021.33.6.593

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Psoriasis is a chronic inflammatory skin disease characterized by accelerated tumor necrosis factor-α (TNF-α) /interleukin (IL) -23/IL-17 axis, epidermal hyperproliferation, and dysregulated differentiation. Psoriasis is occasionally associated with autoimmune liver diseases such as autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), caused by autoimmunity against hepatocyte- or cholangiocyte-specific autoantigens, respectively. Overlap syndrome is a condition in which patients have features of both AIH and PBC. It has been reported that AIH, PBC, or the overlap syndrome can be triggered by certain drug therapies. A 65-year-old Japanese man developed increased serum levels of aspartate and alanine aminotransferases, and positive anti-nuclear and anti-mitochondrial M2 antibodies, along with neutropenia, at 4 weeks of treatment with an anti-IL-17 receptor A antibody brodalumab for generalized pustular psoriasis. Histological evaluation of the liver revealed interface hepatitis and non-suppurative destructive cholangitis, which is compatible with the overlap syndrome of AIH and PBC. This is the first case of AIH/PBC overlap syndrome during treatment with brodalumab for generalized pustular psoriasis. The relationship between brodalumab and AIH/PBC overlap syndrome should be further elucidated. The risk of autoimmune liver diseases in patients with psoriasis treated with brodalumab should be carefully considered.

DOI： 10.1272/jnms.JNMS.2021_88-517

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担当区分：最終著者   記述言語：日本語   出版者・発行元：金原出版(株)  

＜文献概要＞6歳,女児。2歳頃より,頭頸部に紅暈を伴う膿疱がみられ,近医を受診した。真菌・細菌培養陰性で,ステロイド薬外用や抗菌薬内服・外用で治療された。皮疹は出没を繰り返すため,精査目的に当科を紹介受診した。ステロイド薬外用で経過観察していたが,皮疹が拡大し,頸部から胸部,臍周囲の地図状の紅斑局面上に弛緩性膿疱が多発した。初診半年後に膿疱部から生検を施行した。組織学的に角層下に好中球性膿疱がみられ,角層下膿疱症と診断した。ステロイド薬,活性型ビタミンD3外用に反応が乏しく,ジアフェニルスルホン25〜75mg/日およびコルヒチン0.5mg/日を内服して皮疹は軽快した。小児角層下膿疱症では,リスク・ベネフィットを考慮して治療を選択すべきである。

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記述言語：英語  

DOI： 10.1111/1346-8138.15691

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担当区分：最終著者,　責任著者   記述言語：英語  

DOI： 10.1111/1346-8138.15622

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Chronic spontaneous urticaria (CSU) is defined as the spontaneously appearing weals and/or angioedema for more than 6 weeks. Dietary habits can modulate the pathogenesis of CSU. However, dietary intakes of nutrients or food in CSU patients, compared with healthy controls, have not been examined in quality and quantity. METHODS: We evaluated dietary habits in adult Japanese patients with chronic spontaneous urticaria using a validated, brief-type self-administered diet history questionnaire and compared the results to those of age- and sex-matched healthy controls. The severity of CSU was evaluated using the Urticaria Control Test. RESULTS: Japanese CSU patients showed higher body mass indices, higher intakes of eggs, vegetables other than green/yellow vegetables/mushrooms/algae, cholesterol, folic acid, dietary fibres, vitamin D, vitamin K, Cu, Fe, Pi, Ca, Mg, Na and salt, and lower intake of alcohol, compared to controls. The logistic regression analysis showed that CSU was associated with high body mass index and high intake of eggs. The intake of beverages was higher in uncontrolled CSU patients (Urticaria Control Test ≦11 points) than in controlled patients. The logistic regression analysis showed that uncontrolled CSU was associated with high intake of beverages. The intake of coffee, caffeine-rich and non-alcohol beverage, in uncontrolled CSU patients was higher than that in controlled patients. CONCLUSIONS: Chronic spontaneous urticaria was associated with high body mass index and high intake of eggs. Uncontrolled CSU was associated with high intake of beverages. Further studies should elucidate the relationships of these results with the development or exacerbation of CSU.

DOI： 10.1111/ajd.13283

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担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(株)協和企画  

＜文献概要＞症例のポイント ・薬剤誘発性と考えられる表在播種型汗孔角化症(disseminated superficial porokeratosis:DSP)の1例を報告した.・薬疹の発症が,なんらかの機序で汗孔角化症(porokeratosis:PK)の発症を促した可能性がある.今後同様の症例の蓄積による検証が待たれる.

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担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版(株)  

＜文献概要＞70歳,女性。右上腕,右下腿,両大腿に紅色結節が出現した。紅色結節から抗酸菌を検出し,DNA-DNA Hybridization法でMycobacterium abscessusと同定した。クラリスロマイシン400mg/日内服で下肢の結節は治癒した。右上腕の結節は切除し,再発はない。原因菌は後に,PCR法でMycobacterium abscessusの亜種であるMycobacterium abscessus subsp. massilienseと判明した。Mycobacterium abscessusは亜種間で抗菌薬の感受性が異なるが,亜種の鑑別を迅速に行える検査法は存在しないため,治療は多剤併用で開始することが望ましい。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01266&link_issn=&doc_id=20200629100015&doc_link_id=10.18888%2Fhi.0000002045&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000002045&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版(株)  

＜文献概要＞70歳,男性。初診の十数年前から背部に皮膚結節を自覚,徐々に増大し,中央に潰瘍を伴うようになった。淡紅色,弾性硬,中央に潰瘍を伴う15mm大のドーム状皮膚結節があり,ダーモスコピーでは樹枝状血管と潰瘍化,一部に青黒色斑がみられた。病理組織像では,真皮に毛芽細胞様細胞が結節状あるいは索状に増殖し,腫瘍胞巣の辺縁で核の柵状配列,腫瘍胞巣と間質の間に裂隙の形成があり,基底細胞癌と診断した。自験例は日本人の無色素性基底細胞癌としてはまれな躯幹の発症であり,診断に苦慮した。無色素性基底細胞癌のダーモスコピー像では高頻度に樹枝状血管や潰瘍化がみられ,注意深い観察により色素性所見がみられることもあり,診断に有用である。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01266&link_issn=&doc_id=20200512100013&doc_link_id=10.18888%2Fhi.0000001883&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000001883&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report the case of a 59-year-old Japanese woman who developed linear IgA bullous dermatosis during treatment for ulcerative colitis that manifested as pruritic vesicles with erythema on the trunk and scalp. Histopathological examination revealed subepidermal bulla with neutrophil and eosinophil infiltration in the upper dermis. Direct immunofluorescence revealed linear IgA deposits at the basement membrane zone, and indirect immunofluorescence using split skin revealed IgA reaction to the epidermal side (lamina lucida type). We reviewed 33 reported cases of linear IgA bullous dermatosis associated with ulcerative colitis and found that ulcerative colitis preceded the onset of linear IgA bullous dermatosis in 94% of the patients and that IgA-positive patients in split skin indirect immunofluorescence all showed the lamina lucida type, indicating that target antigens for serum IgA antibodies may reside in the lamina lucida. Regarding the pathogenetic association of ulcerative colitis and linear IgA bullous dermatosis, intestinal inflammation may induce the exposure and presentation of intestinal antigens that are cross-reactive to cutaneous antigens, stimulating autoimmune response to antigens of cutaneous basement membrane zones.

DOI： 10.1111/ajd.13121

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Autoimmune hepatitis (AIH) is a chronic inflammation of the liver caused by hepatocyte-specific autoantigens. Psoriasis is a chronic inflammatory skin disease characterized by a skewed interleukin-17 immune response and dysregulated epidermal hyperproliferation and differentiation. Patients with psoriasis have a higher risk of AIH. Some evidence indicates that AIH is triggered by treatment with certain drugs. Brodalumab is a human monoclonal antibody against interleukin-17 receptor A and is used to treat psoriasis. A 70-year-old Japanese man with psoriasis had elevated serum levels of transaminases and bilirubin, positive antinuclear antibodies, and high serum IgG levels after 11 months of brodalumab treatment. Histological analysis of liver tissue revealed interface hepatitis with lymphoplasmacytic infiltration. AIH was diagnosed and treated with prednisolone, which improved his symptoms. This is the first case of AIH during brodalumab treatment for psoriasis. The relationship between brodalumab and AIH should be further examined, and the risk of AIH in psoriatic patients treated with brodalumab should be carefully considered.

DOI： 10.1272/jnms.JNMS.2020_87-607

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 39-year-old Japanese woman presented with a pruritic infiltrated erythematous plaque on the right cheek. Histopathologic analysis of the erythema showed dermal edema, separation of collagen bundles, and nodular perivascular and periadnexal infiltration of lymphocytes in the whole dermis, without epidermal changes. Alcian blue staining intensity was elevated between the collagen bundles, indicating dermal mucinosis. The nodular infiltrates consisted of CD3+ T cell clusters and CD20+ B cell clusters (ratio, approximately 3:1) and included numerous CD123+ cells, indicative of plasmacytoid dendritic cells. Blood analysis revealed serum antinuclear antibody at a titer of 1:160 (homogeneous, speckled pattern). Lupus erythematosus tumidus with pseudolymphomatous infiltrates was diagnosed. Hydroxychloroquine treatment partially improved symptoms; however, the addition of prednisolone was required for complete resolution. Lupus erythematosus tumidus is sometimes accompanied by pseudolymphomatous infiltrates. Dermal mucinosis and the presence of numerous plasmacytoid dendritic cells are useful in differentiating lupus erythematosus tumidus from pseudolymphoma.

DOI： 10.1272/jnms.JNMS.2020_87-208

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担当区分：最終著者,　責任著者   記述言語：英語  

DOI： 10.1111/1346-8138.15081

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担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版(株)  

＜文献概要＞64歳,男性。非活動性B型肝炎ウイルスキャリア。初診時,扁平隆起する紅色小結節が頸部,腰背部,両前腕,両下腿に多発集簇していた。病理組織像は非乾酪性類上皮細胞肉芽腫であった。HBs抗原陽性,HBe抗体陽性。眼底検査で網脈絡膜萎縮を認めた。結節型皮膚サルコイド,眼サルコイドーシスと診断した。初診2ヵ月後,顔面にびまん浸潤型サルコイドと考えられる暗紅色斑が出現した。核酸アナログを併用してプレドニゾロン15mg内服を開始し,皮疹は軽快した。自験例ではB型肝炎ウイルスに対するTh1反応の活性化がサルコイドーシスの肉芽腫形成を誘導した可能性がある。B型肝炎ウイルスキャリアにステロイドを全身投与する場合,ウイルス再活性化防止対策が必要である。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01266&link_issn=&doc_id=20191024130010&doc_link_id=10.18888%2Fhi.0000001620&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000001620&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

担当区分：筆頭著者,　責任著者   記述言語：英語  

DOI： 10.1111/1346-8138.14880

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記述言語：英語  

DOI： 10.1111/1346-8138.14766

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.14728

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that targets the low-density lipoprotein (LDL) receptor for lysosomal degradation. PCSK9 impedes the receptor-mediated clearance of LDL-cholesterol, thereby increasing serum LDL-cholesterol levels. Evolocumab, a human monoclonal antibody against PCSK9, effectively reduces serum LDL-cholesterol levels. We report the first known case of a patient who developed an atopic dermatitis (AD)-like rash during evolocumab therapy. A 43-year-old Japanese man with heterozygous familial hypercholesterolemia was treated with subcutaneous injection of 140 mg evolocumab biweekly, for 16 months. The therapy was then changed to subcutaneous injection of 420 mg evolocumab monthly. A few days after the first dose, the patient experienced pruritus and rash on his extremities. The rash worsened, while the pruritus subsided, then relapsed after the second and third doses. He had erythema and excoriation on his legs, lichenification over his popliteal fossa, xerosis on his forearms, an increased serum IgE level, and a family history of AD in his siblings. We made a provisional diagnosis of AD characterized by enhanced type 2 helper T (Th2) activity and treated him with topical corticosteroids and oral anti-histamines. His rash improved and did not relapse after the fifth dose; however, his LDL-cholesterol level increased. PCSK9 or oxidized LDL activates macrophages or dendritic cells, respectively, and enhances their activity to induce Th1 cells antagonizing Th2 cells. We hypothesized that high-dose evolocumab may suppress Th1 activity to antagonize Th2, and unmask Th2 disposition based on the patient's atopic diathesis, triggering the rash mimicking AD. Clinicians should be aware of rash development during evolocumab therapy.

DOI： 10.1272/jnms.JNMS.2019_86-309

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記述言語：英語  

DOI： 10.1111/1346-8138.14474

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記述言語：英語  

DOI： 10.1111/1346-8138.14119

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Lipocalin-2 (LCN2) is an antimicrobial protein and adipokine associated with insulin resistance, obesity and atherosclerotic disease. Psoriasis is a T-helper (Th)1/Th17-mediated, chronic inflammatory dermatosis related to metabolic syndromes and serum LCN2 levels are elevated in psoriatic patients. We examined the in vivo effects of LCN2 on topical imiquimod (IMQ)-induced psoriasiform skin in BALB/c mice and in vitro on human keratinocytes (KC). Clinically, i.p. injected LCN2 exacerbated erythema and scaling in IMQ-treated murine skin compared with phosphate-buffered saline injection alone, and it augmented interleukin (IL)-17A, IL-17F, IL-22, IL-23p19, IL-12p40, CCL20, tumor necrosis factor-α, chemokine (C-X-C motif) ligand (CXCL)1, CXCL2, DEFB4, DEFB14, LCN2 and S100A7 mRNA levels of IMQ-treated murine skin while it did not increase the mRNA levels of interferon-γ, IL-12p35 or CXCL10. LCN2 in synergy with IL-17 increased mRNA levels of CCL20, LCN2 and DEFB4A but not of CXCL10 in human KC in vitro. These results suggest that LCN2 enhances the expression of Th17 cytokines/chemokines and antimicrobial peptides in murine IMQ-treated psoriatic skin and KC. LCN2 may potentiate the development of psoriasis via the enhancement of Th17- and antimicrobial peptide-mediated inflammation.

DOI： 10.1111/1346-8138.13227

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Contact with fungal pathogens initiates a series of host responses beginning with innate immunity, which leads to fungal recognition and microbial killing. The innate immune system also modulates the adaptive immune responses, leading to the establishment of immunological memory and protection against pathogens. In the case of dimorphic fungi such as Candida albicans and Malassezia, the immune system plays an important role in tolerance and resistance when managing the organisms either as commensal microbiota or invading pathogens, and disruption of this balance can result in pathological consequences for the host. In addition, Malassezia and dermatophytes have immunomodulatory capabilities that allow them to adapt to their environments and they may exert different effects in healthy and diseased skin. Here, we discuss the host immune responses to dermatomycoses caused by dimorphic fungi such as C. albicans and Malassezia as well as dermatophytes such as Trichophyton spp. and Arthroderma benhamiae to gain a better understanding of the mechanisms of the host-dermatomycosis interaction.

DOI： 10.1111/1346-8138.12718

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background Prolactin (PRL) is a pituitary-derived neuropeptide hormone that has been suggested to promote the development of psoriasis, a Th17/Th1-mediated inflammatory dermatosis. PRL increases the expression of Th1 cytokines; however, its effects on Th17 responses are unknown.
Objective This study aims to determine the in vivo effects of PRL on the expression of Th17 cytokines/chemokines in imiquimod-induced psoriasiform skin inflammation in mice.
Methods BALB/c mice were intraperitoneally injected with PRL or phosphate-buffered saline, and imiquimod cream or Vaseline was applied to the shaved back skin for six consecutive days.
Results Intraperitoneal PRL increased the mRNA levels of IL-17A, IL-17F, IL-22, IL-23p19, IL-12p40, CCL20 and STAT3 in imiquimod-treated skin. Mice treated with imiquimod plus PRL, but not those treated with imiquimod plus phosphate-buffered saline, showed significantly increased mRNA levels of TNF-alpha, IFN-gamma, IL-12p35 and CXCL2 compared with controls. Intraperitoneal PRL increased the numbers of CD3(+) and GR-1(+) cells in the dermis of imiquimod-treated skin.
Conclusions These results suggest that intraperitoneal PRL enhances the expression of Th17 and Th1 cytokines/chemokines, and augments inflammation in imiquimod-induced psoriasiform skin. Prolactin may thus exacerbate psoriasis through the enhancement of Th17/Th1 responses.

DOI： 10.1111/jdv.12295

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Malassezia, a lipophilic yeast, exacerbates atopic dermatitis. Malassezia products can penetrate the disintegrated stratum corneum and encounter subcorneal keratinocytes in the skin of atopic dermatitis patients. Type 1 helper T (Th1) cells infiltrate chronic lesions with atopic dermatitis, and antimycotic agents improve its symptoms. We aimed to identify Malassezia-induced chemokines in keratinocytes and examine whether antimycotics suppressed this induction. Normal human keratinocytes were incubated with a Malassezia restricta extract and antimycotics. Chemokine expression was analyzed by enzyme-linked immunosorbent assays and real-time polymerase chain reaction. Signal transducer and activator of transcription (STAT)1 activity was examined by luciferase assays. The tyrosine-phosphorylation of STAT1 was analyzed by western blotting. The M. restricta extract increased the mRNA and protein expression of Th1-attracting CXC chemokine ligand (CXCL)10 and STAT1 activity and phosphorylation in keratinocytes, which was suppressed by a Janus kinase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine suppressed M. restricta extract-induced CXCL10 mRNA and protein expression and STAT1 activity and phosphorylation. These effects were similarly induced by 15-deoxy-Δ-(12,14) -prostaglandin J2 (15d-PGJ2 ), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes. The antimycotic-induced suppression of CXCL10 production and STAT1 activity was counteracted by a lipocalin-type prostaglandin D synthase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine may suppress the M. restricta-induced production of CXCL10 by inhibiting STAT1 through an increase in 15d-PGJ2 production in keratinocytes. These antimycotics may block the Th1-mediated inflammation triggered by Malassezia in the chronic phase of atopic dermatitis.

DOI： 10.1111/1346-8138.12380

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is produced by epidermal keratinocytes, and it induces Th2-mediated inflammation. TSLP expression is enhanced in lesions with atopic dermatitis, and is a therapeutic target. Antimycotic agents improve the symptoms of atopic dermatitis. OBJECTIVE: The objective of this study was to examine whether antimycotics suppress TSLP expression in human keratinocytes. METHODS: Normal human keratinocytes were incubated with polyinosinic-polycytidylic acid (poly I:C) plus IL-4 in the presence of antimycotics. TSLP expression was analyzed by ELISA and real time PCR. Luciferase assays were performed to analyze NF-κB activity. IκBα degradation was analyzed by Western blot analysis. RESULTS: Poly I:C plus IL-4 increased the secretion and mRNA levels of TSLP, which was suppressed by an NF-κB inhibitor, and also enhanced NF-κB transcriptional activities and induced the degradation of IκBα in keratinocytes. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine suppressed the secretion and mRNA expression of TSLP, NF-κB activity, and IκBα degradation induced by poly I:C plus IL-4. These suppressive effects were similarly manifested by 15-deoxy-Δ-(12,14)-PGJ2 (15d-PGJ2), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes and decreased the release of thromboxane B2, a thromboxane A2 metabolite. Antimycotic-induced suppression of TSLP production and NF-κB activity was counteracted by an inhibitor of lipocalin type-prostaglandin D synthase. CONCLUSIONS: Antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine may suppress poly I:C plus IL-4-induced production of TSLP by inhibiting NF-κB via increasing 15d-PGJ2 production in keratinocytes. These antimycotics may block the overexpression of TSLP in lesions with atopic dermatitis.

DOI： 10.1016/j.jdermsci.2013.04.023

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Ciclosporin (Cs)A is an effective treatment for psoriasis. However, to date, the effect of CsA on the production of interleukins (ILs) is unknown. We investigated how CsA affects production of IL-12/23p40 and IL-23 production by the human monocyte cell line, THP-1, which is able to differentiate into macrophage-like cells or normal human keratinocytes (NHKs). THP-1 cells were preincubated with CsA, then stimulated with lipopolysaccharide (LPS), polyinosinic:polycytidylic acid or adenosine triphosphate. The levels of IL-12/23p40 and IL-23 released into the supernatant were assayed by ELISA. CsA significantly reduced both IL-12/23p40 and IL-23 production by LPS-stimulated THP-1 cells, but not in LPS-stimulated macrophage-like differentiated THP-1 cells. None of the stimuli used significantly induced either IL-12/23p40 or IL-23 production in NHKs. CsA inhibits not only IL-12/23p40 and IL-12p70, but also heterodimeric IL-23 production by human monocytes, which may be one possible mechanism for the therapeutic efficacy of CsA in psoriasis.

DOI： 10.1111/ced.12110

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

IL-27, a member of the IL-12 cytokine family, primes Th1 cell differentiation, whereas it suppresses Th17 cell development. We have previously reported that serum IL-27 levels are elevated in psoriatic patients and that IL-27 greatly induces in vitro production of Th1-type chemokines through STAT1 activation. In this study, to further investigate the in vivo role of IL-27 in the pathogenesis of psoriasis, we induced psoriasis-like inflammation on mouse back skin with topical application of imiquimod (IMQ), and continuously injected IL-27 or PBS subcutaneously. IMQ-treated skin showed an increase of IL-27 mRNA levels and the infiltration of IL-27-producing cells in the papillary dermis. The injection of IL-27 to the IMQ-treated skin exacerbated the disease compared with PBS injection. The IL-27 injection further augmented mRNA levels of IFN-γ, CXCL9, CXCL10, CXCL11, and TNF-α, without altering those of IL-17A, IL-17F, IL-22, and CCL20. Finally, IL-27 antagonism attenuated the upregulation of IFN-γ, CXCL9, CXCL10, CXCL11, and TNF-α mRNA levels, and induced clinical and histological improvement in the IMQ-treated skin. These results indicate that IL-27 would act in a proinflammatory manner, and thereby exacerbate the psoriasis-like skin inflammation induced by IMQ.

DOI： 10.1038/jid.2012.313

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担当区分：筆頭著者,　責任著者  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background Skin lesions with atopic dermatitis (AD) are associated with dysregulated expression of LL-37 and enhanced expression of IL-22, thymic stromal lymphopoietin (TSLP), IL-25, IL-31, and oncostatin M. Vitamin D3 enhances LL-37 production in keratinocytes. This study aimed to examine the serum levels of LL-37 and vitamin D3 and their regulation of cytokine production in patients with AD. Methods Serum levels of LL-37 and 25-hydroxyvitamin D3 were analyzed by ELISA. The effects of 1,25-dihydroxyvitamin D3 or LL-37 on cytokine production in T cells or keratinocytes were analyzed by ELISA and real-time PCR. Results Serum levels of LL-37 and 25-hydroxyvitamin D3 were decreased in patients with AD compared to normal donors and were correlated in both groups. Serum levels of LL-37 correlated with those of oncostatin M and IL-31 in normal donors and patients with AD, while 25-hydroxyvitamin D3 levels did so only in normal donors. 1,25-dihydroxyvitamin D3 increased LL-37 production in human keratinocytes and neutrophils. 1,25-dihydroxyvitamin D3 and LL-37 enhanced the oncostatin M and IL-31 production in CD3/28-stimulated T cells, but did not alter IL-25 and TSLP production in TNF-a-stimulated keratinocytes. In CD3/28-stimulated T cells, 1,25-dihydroxyvitamin D3 reduced the IL-22 production, while LL-37 enhanced it. These effects of 1,25-dihydroxyvitamin D3 and LL-37 were suppressed by vitamin D receptor antagonist and pertussis toxin, respectively. Conclusions Systemic vitamin D3 levels are reduced in patients with AD, which may contribute to decreased systemic LL-37 levels. LL-37 may systemically potentiate the oncostatin M and IL-31 production in normal donors and patients with AD, while vitamin D3 may do so only in normal donors.

DOI： 10.1111/j.1398-9995.2012.02824.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

The protein lipocalin (LCN)-2 is known to be related to insulin resistance, obesity and atherosclerotic diseases. Psoriasis is an inflammatory skin disease related to metabolic syndrome. The aim of this study was to examine the relationship between serum LCN2 levels and indicators for metabolic syndrome and inflammatory cytokine levels in patients with psoriasis. Serum LCN2 levels were measured in patients with psoriasis, atopic dermatitis (AD) or bullous pemphigoid (BP), and compared with those of healthy controls. Serum LCN2 levels were also compared with several indicators for metabolic syndrome, and with serum levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-a, two markers of inflammation. Serum LCN2 levels in patients with psoriasis were significantly higher than those of healthy controls, but there was no significant correlation between serum LCN2 and body mass index. Serum LCN2 levels also correlated with serum IL-6 and TNF-a levels in patients with psoriasis. Serum LCN2 levels are a general indicator for increased inflammation in the patients with psoriasis.

DOI： 10.1111/j.1365-2230.2011.04265.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.imbio.2011.10.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/jid.2011.201

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

Psoriasis is an inflammatory dermatosis with enhanced expression of hBD-2 in keratinocytes and infiltration of cytokine-producing T cells, which in turn, up-or down-regulate hBD-2 expression. We determined the serum levels of hBD-2 and cytokines in psoriasis patients and analyzed the effects of hBD-2 on cytokine production in human peripheral blood T cells. Serum hBD-2 levels in patients were higher than those in controls and correlated with PASI, serum IFN-gamma, and IL-10 levels and correlated inversely with serum IL-17 levels. IFN-gamma, IL-17, IL-22, TNF-alpha, IL-1 beta, and IL-6 enhanced, and IL-10, IL-4, and IL-13 suppressed hBD-2 secretion from keratinocytes. hBD-2 enhanced secretion and mRNA levels of IFN-gamma, TNF-alpha, IL-10, IL-1 beta, IL-6, and IL-22 and reduced those of IL-17 in CD3/28-stimulated T cells. These effects of hBD-2 were counteracted by PTX. hBD-2 induced phosphorylation of JNK, ERK, and Akt in T cells. Inhibitors of these signals attenuated hBD-2-induced production of IFN-gamma, TNF-alpha, IL-10, IL-1 beta, IL-6, and IL-22. hBD-2 suppressed phosphorylation of STAT3 and enhanced expression of SOCS3 in CD3/28-stimulated T cells. siRNA against SOCS3 reversed hBD-2-induced suppression of IL-17 production and STAT3 phosphorylation. JNK and MEK inhibitors suppressed hBD-2-induced expression of SOCS3. In conclusion, hBD-2 may bind PTX-sensitive GPCR(s) on T cells and act as a stimulator by enhancing IFN-gamma, TNF-alpha, IL-1 beta, IL-6, and IL-22 production via JNK, MEK/ERK, and PI3K/Akt and as a regulator by suppressing IL-17 production via SOCS3 or by stimulating IL-10 production. J. Leukoc. Biol. 89: 935-944; 2011.

DOI： 10.1189/jlb.0111004

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

The antimicrobial peptide human beta-defensin-3 (hBD-3) is produced by epidermal keratinocytes, and exhibits broad killing activity against bacteria or fungi. Prostaglandin D(2) enhances hBD-3 production in human keratinocytes by stimulating a transcription factor, activator protein-1 via chemoattractant receptor-homologous molecule expressed on T helper 2 cells (CRTH2). Prostaglandin H(2), a precursor of prostaglandin D(2) can be converted to thromboxane A(2). Certain antimycotic drugs act on keratinocytes and modulate their production of chemokines. In this in vitro study, we examined the effects of antimycotics on hBD-3 production in human keratinocytes. Antimycotics itraconazole and terbinafine hydrochloride increased hBD-3 secretion and mRNA levels in parallel to the enhanced activity of activator protein-1, expression and phosphorylation of activator protein-1 component, c-Fos, but fluconazole was ineffective. These effects were abrogated by CRTH2 antagonist. Itraconazole and terbinafine hydrochloride increased prostaglandin D(2) release from keratinocytes and reduced the release of thromboxane B(2), a thromboxane A(2) metabolite. The conditioned medium from itraconazole or terbinafine hydrochloride-treated keratinocytes inhibited the growth of Candida albicans dependently on hBD-3. These results suggest that itraconazole and terbinafine hydrochloride may enhance c-Fos expression and phosphorylation, activator protein-1 activity and hBD-3 production by increasing prostaglandin D(2) release from keratinocytes. These antimycotic drugs may suppress thromboxane A(2) synthesis and redirect the conversion of prostaglandin H(2) towards prostaglandin D(2). The induction of hBD-3 in keratinocytes is another possible mechanism for the antimycrobial effects of these drugs, which may augment the cutaneous defense activity against infection. (C) 2010 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.imbio.2010.08.008

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1111/j.1365-2133.2010.10123.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Expression of leucine leucine-37 (LL-37) is enhanced in keratinocytes of skin lesions with psoriasis We examined cerum LL-37 levels in patients with psoriasis vulgans Serum LL-37 levels in patients were higher than in normal controls and were reduced after cyclosponne A treatment In both groups LL 37 and interleukin (IL)-17 levels inversely correlated In patients LL-37 levels correlated with interferon (IFN)-gamma and IL-10 levels In controls LL 37 levels inversely correlated with tumor necrosis factor (TNF)-alpha IL-6 IL-1 beta and IL-22 levels IFN-gamma IL-17 IL-22 TNF-alpha IL-6 and IL-1 beta enhanced and IL-10 IL-4 IL-13 and cyclosponne A suppressed LL-37 secretion from kerannocytes and neutrophils LL-37 enhanced IFN-gamma IL-4 IL-13 and TNF-alpha secretion from CD3/CD28-stimulated T cells suppressed TNF-alpha IL-1 beta IL-6 and IL-10 secretion from lipopolysacchande-stimulated monocytes and IL-17 IL-22 IL-1 beta IL-6 and IL-10 secretion from CD3/CD28-stimulated T cells LL-37 may sustain its production by enhancing IFN-gamma or reducing IL-10 production while suppressing its production by reducing IL 17 IL-22 TNF-alpha IL-1 beta or IL-6 and enhancing IL-4 or IL-13 production In patients systemic LL-37 production is enhanced and an IFN-gamma/LL-37-posinve feedback loop may exist In controls negative feedback by LL-37 on TNF-alpha IL-1 beta IL-22 and IL-6 may exist In both groups negative feedback by LL-37 on IL-17 may exist LL-37 may act as an effector and regulator (C) 2010 American Society for Histocompatibility and Immunogenetics Published by Elsevier Inc All rights reserved

DOI： 10.1016/j.humimm.2010.09.005

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

The antimicrobial peptide human beta-defensin-3 (hBD-3) is produced by epidermal keratinocytes and protects the skin from infections. This peptide induces the release of a lipid mediator, prostaglandin D-2 from dermal mast cells. Prostaglandin D-2 binds to cell-surface G protein-coupled receptors, D prostanoid receptor, and chemoattractant receptor-homologous molecule expressed on T helper cell type 2 (CRTH2). Both receptors are detected on epidermal keratinocytes. It is reported that prostaglandin D-2 is involved in cutaneous allergy, however, its role in antimicrobial defense is unknown. We examined the in vitro effects of prostaglandin D-2 on hBD-3 production in normal human keratinocytes. Prostaglandin D-2 enhanced hBD-3 secretion and mRNA expression in human keratinocytes. Prostaglandin D-2-induced hBD-3 production was suppressed by the CRTH2 antagonist ramatroban and by antisense oligonucleotides against c-Jun and c-Fos, components of a transcription factor, activator protein-1 (AP-1). Prostaglandin D-2 enhanced the transcriptional activity and DNA binding of AP-1, expression, phosphorylation, and DNA binding of c-Fos proteins in keratinocytes. Prostaglandin D-2-induced hBD-3 production, AP-1 activity, and c-Fos expression and phosphorylation were suppressed by 00126, PP2, and pertussis toxin, which are inhibitors of mitogen-activated protein kinase kinase (MEK), src, and G; proteins, respectively. The phosphorylation of extracellular signal-regulated kinase (ERK), downstream kinase of MEK, was induced by prostaglandin D-2, and suppressed by ramatroban, pertussis toxin, PP2, and U0126. These results suggest that prostaglandin D-2 induces hBD-3 production in human keratinocytes by activating AP-1 through the expression and phosphorylation of c-Fos via the CRTH2/G(i)/src/MEK/ERK pathway. Prostaglandin D-2 may promote cutaneous antimicrobial activity via hBD-3. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bcp.2009.11.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

The immunological significance of IL-27 has been reported and discussed in various Th1/Th17-mediated inflammatory diseases. However, its importance in psoriasis is unknown. We investigated pathophysiological roles of IL-27 in psoriasis in this study. Serum IL-27 levels in psoriatic patients were significantly higher than those in healthy controls, and correlated with disease severity and serum IFN-gamma levels. An immunohistochemical analysis revealed the infiltration of IL-27-secreting cells in the papillary dermis of psoriatic skin lesions but not in skin lesions with atopic dermatitis or normal skin. Furthermore, IL-27 alone greatly induced in vitro CXCL9, CXCL10, and CXCL11 production and tyrosine phosphorylation of signal transducer and activator of transcription 1 in normal human keratinocytes, while it suppressed the tumor necrosis factor-alpha-induced production of IL-1 alpha and CCL20. These results indicate that IL-27 may promote the onset of psoriasis, while it may simultaneously attenuate the expanded inflammation in this disease. Our results implicate potential therapeutic effects of IL-27 for psoriasis.

DOI： 10.1038/jid.2009.349

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: The antimicrobial peptide human beta-defensin-3 (hBD-3) is produced by epidermal keratinocytes, and promotes cutaneous antimicrobial defense, inflammation, and wound repair. hBD-3 induces histamine release from mast cells. We previously showed that histamine enhanced transcriptional activity of activator protein-1 (AP-1) in human keratinocytes by inducing the expression of AP-1 component c-Fos via the activation of extracellular signal-regulated kinase (ERK) through HI receptors.
Objective: To examine in vitro effects of histamine on hBD-3 production in normal human keratinocytes.
Methods: The hBD-3 production was examined by enzyme-linked immunosorbent assays and reverse transcription-polymerase chain reaction. The transcriptional activities were analyzed by dual luciferase assays. The phosphorylation of proteins was examined by Western blotting.
Results: Histamine enhanced hBD-3 secretion and mRNA expression in keratinocytes. The histamine-induced hBD-3 production was suppressed by H I antagonist pyrilamine and antisense oligonucleotides against signal transducer and activator of transcription 3 (STAT3) and AP-1 components c-Jun and c-Fos. Histamine enhanced STAT3 transcriptional activity and induced tyrosine and serine phosphorylation of STAT3. The former was suppressed by Janus kinase 2 (JAK2) inhibitor AG490, while the latter was suppressed by mitogen-activated protein kinase kinase (MEK) inhibitor PD98059; both were suppressed by pyrilamine. AG490 and PD98059 suppressed histamine-induced hBD-3 production and STAT3 activity. Histamine induced tyrosine phosphorylation of JAK2, and pyrilamine suppressed the phosphorylation.
Conclusion: It is suggested that histamine induces hBD-3 production in human keratinocytes through H I receptors by activating STAT3 and AP-1 via JAK2 and MEK/ERK. Histamine may promote cutaneous antimicrobial defense, inflammation, and wound repair through hBD-3. (C) 2009 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.jdermsci.2009.07.012

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記述言語：英語   出版者・発行元：JOHN LIBBEY EUROTEXT LTD  

DOI： 10.1684/ejd.2009.0773

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Extracts of Dioscorea coomposita or Dioscorea villosa are consumed as supplemental health foods at the time of climacteric. The extracts contain large amounts of the plant steroid, diosgenin. Here, we studied the safety and efficacy of diosgenin against skin aging at the time of climacteric. In vitro, diosgenin enhanced DNA synthesis in a human 3D skin equivalent model, and increased bromodeoxyuridine uptake and intracellular cAMP level in adult human keratinocytes. The increase of bromodeoxyuridine uptake by diosgenin was blocked by an adenylate cyclase inhibitor, but not by antisense oligonucleotides against estrogen receptor alpha, estrogen receptor beta or an orphan G-protein-coupled receptor, GPR30, indicating the involvement of cAMP but not estrogen receptor alpha, estrogen receptor beta or GPR30. In vivo, administration of diosgenin improved the epidermal thickness in the ovariectomized mice, a climacteric model, without altering the degree of fat accumulation. in order to examine the safety of diosgenin, diosgenin and 17 beta-estradiol were administered to breast cancer-burdened mice. The results revealed that while 17 beta-estradiol accelerated the tumor growth, diosgenin did not show this effect. Our finding, a restoration of keratinocyte proliferation in aged skin, suggests that diosgenin may have potential as a safe health food for climacteric. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.steroids.2009.01.006

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-V C H VERLAG GMBH  

Psoriasis vulgaris is an autoimmune dermatosis with Th17 infiltration. Prolactin (PRL) may participate in the pathogenesis of psoriasis. The chemokine CCL20 recruits Th17 cells, and CCL20 production by epidermal keratinocytes is enhanced in psoriatic lesions. We examined the in vitro effects of PRL on CCL20 production in human keratinocytes. PRL increased basal and IL-17-induced CCL20 secretion, and mRNA expression in keratinocytes. CCL20 production by PRL was suppressed by antisense oligonucleotides against the AP-1 components c-Fos and c-jun, whereas that by IL-17 was suppressed by antisense NF-kappa B p50 and p65. CCL20 production induced by PRL plus IL-17 was suppressed by antisense c-Fos, c-jun, p50, and p65. PRL alone increased the transcriptional activity of AP-1, and c-Fos and c-jun expression; moderately enhanced NF-kappa B activity and I kappa B alpha phosphorylation; and potently increased IL-17-induced NF-kappa B activity. MEK and JNK inhibitors suppressed PRL- or PRL-plus-IL-17-induced CCL20 production and AP-1 activities. MEK inhibitor suppressed PRL-induced c-Fos expression, whereas JNK inhibitor suppressed c-jun expression. PRL induced ERK and JNK phosphorylation. These results suggest that PRL may enhance basal and IL-17-induced CCL20 production in keratinocytes by AP-1 and NF-kappa B activation, which is partially mediated via MEK/ERK and JNK. PRL may promote Th17 infiltration into psoriatic lesions via CCL20.

DOI： 10.1002/eji.200838852

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Anti-cyclic citrullinated peptide antibodies (anti-CCP) are reported to be found in 5-13% of patients with psoriatic arthritis (PsA). However, whether anti-CCP-positive PsA patients and rheumatoid arthritis (RA) patients have a similar pathophysiological background still remains uncertain.
Objective: To determine the prevalence of anti-CCP antibodies in patients with PsA and characterize these anti-CCP-positive patients of PsA.
Methods: We measured the serum levels of the anti-CCP antibodies in patients with PsA (n = 16), psoriasis (n = 15), RA (n = 9) and healthy controls (n = 11). Serum levels of rheumatoid factor (RF), matrix metalloproteinase-3 (MMP-3), cartilage oligomeric matrix protein (COMP), interleukin (IL)-23p19 and IL-12p40 were also measured in all the samples.
Results: Two of the 16 PsA patients (13%) were positive for anti-CCP antibodies with high titers of RF. However, the serum IL-23p19 levels were two orders of magnitude higher in the anti-CCP-positive PsA patients as compared with those in the RA patients and anti-CCP-negative PsA patients. No significant elevation of the serum levels of MMP-3, COMP and IL-12p40 was found in these patients.
Conclusion: Thirteen percent of the PsA patients were positive for anti-CCP. These patients do not fulfill the American College of Rheumatology (ACR) classification criteria for RA so far. Furthermore, they showed the typical clinical features of PsA rather than those of RA. Although anti-CCP-positive PsA patients may possibly be have a risk of developing RA, we propose that these patients be classified, for the moment, into a independent subtype of PsA, as a different entity from RA. (c) 2008 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.jdermsci.2008.06.008

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-V C H VERLAG GMBH  

IL-12, IL-23, and IL-27, which are produced by APC, modulate innate and adaptive immunities. Human beta-defensin-2 (hBD-2) produced by epidermal keratinocytes promotes cutaneous antimicrobial defense and inflammation. We examined the in vitro effects of IL-12, IL-23, and IL-27 on hBD-2 production in human keratinocytes. IL-12, IL-23, and IL-27 enhanced IL-1 beta-induced hBD-2 secretion and mRNA expression in keratinocytes. The stimulatory effects of IL-12, IL-23, and IL-27 were suppressed by antisense oligonucleotides against NF-kappa B p50 and p65. In addition, the effects of IL-12 and IL-27 were suppressed by antisense STAT3 and STAT1, respectively. All the three IL enhanced the basal and IL-1 beta-induced transcriptional activities of NF-kappa B, while IL-12 and IL-27 enhanced STAT3 and STAT1 activities, respectively. Further, IL-12, IL-23, and IL-27 promoted basal and IL-1 beta-induced phosphorylation of I kappa B alpha. IL-12 and IL-23 tyrosine phosphorylated STAT3 and STAT1, respectively; IL-12, IL-23, and IL-27 tyrosine phosphorylated JAK2 and tyrosine kinase-2; and IL-27 tyrosine phosphorylated JAK1. These results suggest that IL-12, IL-23, and IL-27 may enhance IL-1 beta-induced hBD-2 production in keratinocytes by activating NF-kappa B. STAT3 and STAT1 are involved in the effects of IL-12 and IL-27, respectively. Thus, IL-12, IL-23, and IL-27 may promote cutaneous antimicrobial defense and inflammation via hBD-2.

DOI： 10.1002/eji.200738OS1

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Histamine enhances the production of human beta-defensin-2 in human keratinocytes. Am J Physiol Cell Physiol 293: C1916-C1923, 2007. First published October 10, 2007; doi: 10.1152/ajpcell.00293.2007. -The anti-microbial peptide human beta-defensin-2 (hBD-2), produced by epidermal keratinocytes, plays pivotal roles in anti- microbial defense, inflammatory dermatoses, and wound repair. hBD-2 induces histamine release from mast cells. We examined the in vitro effects of histamine on hBD-2 production in normal human keratinocytes. Histamine enhanced TNF-alpha-or IFN-gamma-induced hBD-2 secretion and mRNA expression. Histamine alone enhanced transcriptional activities of NF-kappa B and activator protein-1 (AP-1) and potentiated TNF-alpha-induced NF-kappa B and AP-1 activities or IFN-alpha-induced NF-kappa B and STAT1 activities. Antisense oligonucleotides against NF-kappa B components p50 and p65, AP- 1 components c- Jun and c- Fos, or H1 antagonist pyrilamine suppressed hBD- 2 production induced by histamine plus TNF- alpha or IFN-gamma. Antisense oligonucleotide against STAT1 only suppressed hBD- 2 production induced by histamine plus IFN-gamma. Histamine induced serine phosphorylation of inhibitory NF-kappa B alpha ( I kappa B alpha) alone or together with TNF-alpha or IFN-gamma. Histamine induced c- Fos mRNA expression alone or together with TNF-alpha, whereas it did not further increase c- Jun mRNA levels enhanced by TNF-gamma. Histamine induced serine phosphorylation of STAT1 alone or together with IFN-alpha, whereas it did not further enhance IFN-gamma- induced tyrosine phosphorylation of STAT1. The histamine- induced serine phosphorylation of STAT1 was suppressed by MAPKK (MEK) inhibitor PD98059. These results suggest that histamine stimulates H1 receptor and potentiates TNF-alpha-or IFN-gamma-induced hBD-2 production dependent on NF-kappa B, AP-1, or STAT1 in human keratinocytes. Histamine may potentiate anti- microbial defense, skin inflammation, and wound repair via the induction of hBD-2.

DOI： 10.1152/ajpcell.00293.2007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Dermatophytosis (tinea) is a common disease in superficial mycoses and is generally confined to the stratum corneum in the epidermis and cutaneous appendages. The mechanisms by which dermatophytes cause dermatophytosis, however, are poorly understood. In this study, we evaluated the effect of Trichophyton mentagrophytes, T. tonsurans and T. rubrum on cytokine production by normal human epidermal keratinocytes (NHEKs). After 3-24 h of co-culture of NHEKs with each of the dermatophytes, cytokines in the supernatant were measured by enzyme-linked immunosorbent assay. Promoter activity of IL-8 was measured by chloramphenicol acetyl transferase (CAT) assay. IL-8 and GRO-alpha levels were higher in supernatants co-cultured with T. mentagrophytes isolates from animal than in those with T. mentagrophytes isolates from human, and with T. tonsurans and T. rubrum isolates. CAT expression for IL-8 promoter activity was higher in cell lysates stimulated with T. mentagrophytes isolates from animal than in those with T. mentagrophytes isolates from human, and with T. tonsurans and T. rubrum isolates. These findings suggest that dermatophytes directly induce production of cytokines at the transcriptional level by human keratinocytes, and that there are differences in their ability to induce cytokine production between the dermatophytes.

DOI： 10.1007/s00403-007-0780-7

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Background A chemokine CCL27 recruits skin-homing T cells. CCL27 production by epidermal keratinocytes is dependent on nuclear factor-kappa B (NF-kappa B) activity and is enhanced in lesions with atopic dermatitis or allergic contact dermatitis. A lipid mediator leukotriene B-4 (LTB4) may be involved in the development of these allergic dermatoses. LTB4 acts on cell surface G-protein-coupled receptors, BLT1 and BLT2.
Objective The aim of this study was to investigate the in vitro effects of LTB4 on CCL27 production in human keratinocytes.
Methods Keratinocytes were incubated with TNF-alpha and LTB4. CCL27 secretion and mRNA levels were analysed by ELISA and RT-PCR, respectively. NF-kappa B activities were analysed by luciferase assays. Protein levels or phosphorylation status were analysed by cell-based ELISA.
Results LTB4 alone did not enhance CCL27 production and modestly enhanced NF-kappa B activity in human keratinocytes. However, LTB4 potently enhanced TNF-alpha-induced CCL27 secretion and mRNA expression and NF-kappa B activity. LTB4 alone or together with TNF-alpha, induced phosphorylation and degradation of inhibitory NF-kappa B alpha (I kappa B alpha) and phosphorylation of NF-kappa B p65. These effects of LTB4 were suppressed by BLT1 antagonist U75302, pertussis toxin, phosphoinositide-3 kinase (PI3K) inhibitor LY294002 and extracellular signal-regulated kinase (ERK) kinase inhibitor U0126, but not by BLT2 antagonist LY255283. LTB4 induced phosphorylation of ERK and Akt, downstream kinase of PI3K; LY294002 suppressed phosphorylation of both kinases while U0126 suppressed only the former.
Conclusions These results suggest that LTB4 may enhance TNF-alpha-induced CCL27 production by activating NF-kappa B via the BLT1/G(i/o)/PI3K/ERK pathway in human keratinocytes. LTB4 may contribute to the enhanced CCL27 production of keratinocytes in lesions with atopic dermatitis or allergic contact dermatitis.

DOI： 10.1111/j.1365-2222.2007.02743.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ENDOCRINE SOC  

Psoriasis vulgaris is an autoimmune dermatosis characterized by type 1 T cell infiltration. Prolactin may be involved in the pathogenesis of psoriasis. CXC ligand 9 (CXCL9), CXCL10, and CXCL11 recruit type 1 T cells, and their production by keratinocytes is enhanced in psoriatic lesions. CXCL9, CXCL10, and CXCL11 production by keratinocytes depends on nuclear factor-kappa B (NF-kappa B) and signal transducer and activator of transcription ( STAT) 1 and that of CXCL11 depends on interferon (IFN)-regulatory factor (IRF)-1. We examined in vitro effects of prolactin on CXCL9, CXCL10, and CXCL11 production in human keratinocytes. Although prolactin alone was ineffective, it enhanced IFN-gamma-induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in parallel to the activation of STAT1, NF-kappa B, and IRF-1. Inhibitors of Janus kinase (JAK), p38 MAPK, and MAPK/ERK kinase (MEK) suppressed prolactin-plus IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production and NF-kappa B, STAT1, and IRF-1 activities. Prolactin induced phosphorylation of JAK2 and ERK, whereas IFN-gamma induced phosphorylation of JAK1, JAK2, and p38 MAPK. Prolactin modestly or IFN-gamma greatly induced tyrosine phosphorylation of STAT1, and both were suppressed by JAK inhibitor. Prolactin modestly or IFN-gamma greatly induced serine phosphorylation of STAT1, which was suppressed by MEK or p38 MAPK inhibitor, respectively. Prolactin induced phosphorylation of inhibitory kappa B alpha and NF-kappa B p65, which was suppressed by MEK inhibitor. These results suggest that prolactin may enhance IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in keratinocytes via activation of STAT1, NF-kappa B, and IRF-1 through JAK2 and MEK/ERK pathways. Prolactin may promote type 1 T cell infiltration into psoriatic lesions via these chemokines.

DOI： 10.1210/cn.2006-1639

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-V C H VERLAG GMBH  

IL-18 is involved in the pathogenesis of atopic dermatitis, psoriasis, and allergic contact dermatitis. CXCL9, CXCL10, and CXCL11 recruit type 1 T cells, and the production of these chemokines by keratinocytes is enhanced in these dermatoses. We examined the in vitro effects of IL-18 on IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in human keratinocytes. IL-18 enhanced the IFN-gamma-induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in parallel to the activation of NF-kappa B, STAT1, and IFN-regulatory factor (IRF)-1. Antisense oligonucleotides against NF-kappa B p50, p65, or STAT1 suppressed CXCL9, CXCL10, and CXCL11 production, and antisense IRF-1 suppressed CXCL11 production. Inhibitors of PI3 K, p38 MAPK, and MEK suppressed IL-18 plus IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production and NF-kappa B, STAT1, and IRF-1 activities. IL-18 induced phosphorylation of ERK and Akt, while IFN-gamma induced phosphorylation of p38 MAPK. These results suggest that IL-18 may potentiate IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in keratinocytes by activating NF-kappa B, STAT1., or IRF-1 through PI3 K/Akt and MEK/ERK pathways. These effects of IL-18 may promote the infiltration of type 1 T cells into lesions with inflammatory dermatoses and amplify the skin inflammation. IL-18 may act as a proinflammatory cytokine in these dermatoses and thus is a candidate therapeutic target.

DOI： 10.1002/eji.200636420

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Antimycotic agents are reported to improve cutaneous symptoms of atopic dermatitis or psoriasis vulgaris. Keratinocytes in these lesions excessively produce chemokines, CCL27, CCL2, or CCL5 which trigger inflammatory infiltrates. Tumor necrosis factor-alpha (TNF-alpha) induces production of these chemokines via activating nuclear factor-kappa B (NF-kappa B). We examined in vitro effects of antimycotics on TNF-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes. Antimycotics ketoconazole and terbinafine hydrochloride suppressed TNF-a-induced CCL27, CCL2, and CCL5 secretion and mRNA expression in keratinocytes in parallel to the inhibition of NF-kappa B activity while fluconazole was ineffective. Anti-prostaglandin E-2 (PGE(2)) antiserum or antisense oligonucleotides against PGE(2) receptor EP2 or EP3 abrogated inhibitory effects of ketoconazole and terbinafine hydrochloride on TNF-alpha-induced NF-kappa B activity and CCL27, CCL2, and CCL5 production, indicating the involvement of endogenous PGE(2) in the inhibitory effects. Prostaglandin H-2, a precursor of PGE(2) can be converted to thromboxane A(2). Ketoconazole, terbinafine hydrochloride and thromboxane A(2) synthase (EC 5.3.99.5) inhibitor, carboxyheptyl imidazole increased PGE2 release from keratinocytes and reduced that of thromboxane B-2, a stable metabolite of thromboxane A(2). Carboxyheptyl imidazole also suppressed TNF-alpha-induced NF-kappa B activity and CCL27, CCL2, and CCL5 production. These results suggest that ketoconazole and terbinafine hydrochloride may suppress TNF-alpha-induced NF-kappa B activity and CCL27, CCL2, and CCL5 production by increasing PGE(2) release from keratinocytes. These antimycotics may suppress thromboxane A(2) synthesis and redirect the conversion of PGH2 toward PGE(2). These antimycotics may alleviate inflammatory infiltration in atopic dermatitis or psoriasis vulgaris by suppressing chemokine production. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bcp.2006.05.001

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

Atopic dermatitis is characterized by increased skin innervation. The expression of neurotrophin-4 is enhanced in the epidermal keratinocytes of lesions with atopic dermatitis and may be related to hyperinnervation in these lesions. Prostaglandin E-2 (PGE(2)) levels are increased in lesions with atopic dermatitis; thus, PGE(2) may be involved in the development of this disease. We examined the in vitro effects of PGE(2) on neurotrophin-4 production in human keratinocytes. PGE(2) and EP1/ EP3 agonist sulprostone increased neurotrophin-4 secretion and mRNA levels without altering its mRNA stability. Antisense Sp1 oligode-oxynucleotide and Sp1 inhibitor mithramycin A suppressed PGE(2) and sulprostone-induced neurotrophin-4 expression, indicating the requirement for Sp1 for expression. PGE(2) or sulprostone markedly enhanced the phosphorylation, DNA binding, and transcriptional activity of Sp1 and modestly increased Sp1 mRNA and protein levels. PGE(2) or sulprostone induced the membrane translocation of protein kinase C alpha and the phosphorylation of extracellular signal-regulated kinase (ERK). PGE(2)-induced increases in neurotrophin-4 expression, Sp1 transcriptional and DNA-binding activity, Sp1 mRNA and protein levels, and ERK phosphorylation were suppressed by antisense EP3 oligodeoxynucleotide, inhibitors of phosphatidyli-nositol-specific phospholipase C, conventional protein kinase C, and mitogen-activated protein kinase/ERK kinase 1 (MEK1). These results suggest that PGE(2) enhances neurotrophin-4 production by activating Sp1 via the EP3/ phosphatidylinositol-specific phospholipase C/protein kinase C alpha/MEK1/ERK pathway. PGE(2) may promote innervation in skin lesions with atopic dermatitis via the induction of neurotrophin-4.

DOI： 10.1124/jpet.105.091645

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC VET SCI  

We demonstrated that Demodex canis was transferred to skin xenografts of a dog and a hamster onto severe combined immunodeficiency mice. After the transfer of mites, the number of eggs, larvae, nymphs and adult mites per grain of canine and hamster xenografts increased, whereas no live mites were detected on murine allograft. These results indicate that D. canis proliferates in hair follicles of dog and hamster skins but not in murine allograft. Therefore, D. canis may have host preference but not strict host-specificity.

DOI： 10.1292/jvms.67.445

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) enhances reepithelialization in wounds. Estrogen is known to promote cutaneous wound repair. We examined the in vitro effects of 17 beta-estradiol (E-2) on HB-EGF production by human keratinocytes. E-2 or membrane-impermeable BSA-conjugated E-2 (E-2-BSA) increased HB-EGF secretion, mRNA level, and promoter activity in keratinocytes. E-2 or E-2-BSA enhanced in vitro wound closure in keratinocytes, and the closure was suppressed by anti-HB-EGF antibody. Activator protein-1 (AP-1) and specificity protein 1 (Sp1) sites on HB-EGF promoter were responsible for the E-2- or E-2-BSA-induced transactivation. Antisense oligonucleotides against c-Fos, c-Jun, and Sp1 blocked E-2- or E-2-BSA-induced HB-EGF transactivation. E-2 or E-2-BSA enhanced DNA binding and transcriptional activity of AP- 1 and generated c-Fos/c-Jun heterodimers by inducing c-Fos expression. E-2 or E-2-BSA enhanced DNA binding and transcriptional activity of Sp1 in parallel with the enhancement of Sp1 phosphorylation. These effects of E2 or E-2-BSA were not blocked by the nuclear estrogen receptor antagonist ICI-182,780 or anti-estrogen receptor-alpha or -beta antibodies but were blocked by inhibitors of G protein, phosphatidylinositol-specific PLC, PKC-alpha, and MEK1. These results suggest that E-2 or E-2-BSA may enhance HB-EGF production via activation of AP- 1 and Sp1. These effects of E-2 or E-2-BSA may be dependent on membrane G protein-coupled receptors different from nuclear estrogen receptors and on the receptor-mediated activities of phosphatidylinositol-specific PLC, PKC-alpha, and MEK1. E2 may enhance wound reepithelialization by promoting HB- EGF production in keratinocytes.

DOI： 10.1152/ajpcell.00483.2004

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

Estrogen is reported to prevent age-associated epidermal thinning in the skin. We examined if 17beta-estradiol (E2) may enhance the growth of human keratinocytes, focusing on its effects on the expression of cell cycle-regulatory proteins. E2 enhanced proliferation, bromodeoxyuridine incorporation of keratinocytes, and increased the proportion of cells in the S phase. The E2-induced stimulation of proliferation and bromodeoxyuridine incorporation was suppressed by antisense oligonucleotide against cyclin D2, which induces G(1) to S phase progression. E2 increased protein and mRNA levels of cyclin D2, and resultantly enhanced assembly and kinase activities of cyclin D2-cyclin-dependent kinases 4 or 6 complexes. E2 enhanced cyclin D2 promoter activity, and the element homologous to cAMP response element (CRE) on the promoter was responsible for the effect. Cyclin D2 expression was enhanced by antiestrogens, ICI 182,780 and 4-hydroxytamoxifen, and membrane-impermeable bovine serum albumin-conjugated E2, indicating the effects via membrane E2-binding sites. E2 increased the enhancer activity of CRE-like element and the amount of phosphorylated cAMP response element binding protein (CREB) binding this element, and the increases were suppressed by H-89, an inhibitor of cAMP-dependent protein kinase A. H-89 also suppressed E2-induced cyclin D2 expression, proliferation, and bromodeoxyuridine incorporation in keratinocytes. Antisense oligonucleotide against G-protein-coupled receptor GPR30 suppressed the E2-induced increases of phosphorylated CREB, cyclin D2 level, proliferation, and bromodeoxyuridine incorporation in keratinocytes. These results suggest that E2 may stimulate the growth of keratinocytes by inducing cyclin D2 expression via CREB phosphorylation by protein kinase A, dependent on cAMP. These effects of E2 may be mediated via cell surface GPR30.

DOI： 10.1111/j.0022-202X.2004.12645.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is effective for impaired wound repair. Estrogen is known to enhance wound repair. We examined if 17beta-estradiol (E2) may in vitro enhance GM-CSF production in human keratinocytes. E2 and membrane-impermeable bovine serum albumin-conjugated E2 increased GM-CSF secretion, mRNA stability, and promoter activity. The element homologous to activator protein-1 (AP-1) on the promoter was responsible for the activation. E2 enhanced transcriptional activity and DNA binding of AP-1. E2 transiently generated c-Fos protein, and shifted AP-1 composition from c-Jun homodimers to c-Fos/c-Jun heterodimers in keratinocytes. E2-induced enhancement of GM-CSF secretion, mRNA stability, and promoter activity were not suppressed by estrogen receptor antagonist ICI 182,780, however, suppressed by conventional protein kinase C inhibitor Go6976 and PD98059, an inhibitor of mitogen-activated protein kinase kinase (MEK). Go6976 and PD98059 suppressed E2-induced c-Fos expression and enhancement of DNA-binding and transcriptional activity at AP-1. E2 induced membrane translocation of protein kinase Calpha, which was suppressed by phosphatidylinositol (PI)-specific phospholipase C (PLC) inhibitor U73122. E2 stimulated the phosphorylation of extracellular signal-regulated kinase (ERK), which was suppressed by PD98059, Go6976, and U73122. E2 transiently generated inositol 1,4,5-triphosphate in keratinocytes, which was suppressed by U73122 and guanine nucleotide-binding protein inhibitor. These results suggest that E2 may enhance GM-CSF production via guanine nucleotide-binding protein-coupled membrane receptors and signaling cascade of PI-specific PLC/protein kinase Calpha/MEK/ERK.

DOI： 10.1111/j.0022-202X.2004.23231.x

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The Japanese Society for Medical Mycology  

アトピー性皮膚炎患者の治療に抗真菌薬が有効であることが報告されている.アトピー性皮膚炎患者および健常者の末梢血T細胞の抗CD3,CD28抗体刺激によるTh1,Th2サイトカイン産生に対する抗真菌薬の作用について検討した.抗CD3,CD28抗体で刺激したT細胞のIL-4,IL-5の放出量はアトピー性皮膚炎患者では健常者と比較して高かった.アゾール系抗真菌薬ケトコナゾール,イトラコナゾール,ミコナゾール,非アゾール系抗真菌薬テルビナフィン,トルナフタートはアトピー性皮膚炎患者および健常者T細胞のIL-4,IL-5の放出を抑制したが,IFN-γ,IL-2の放出は抑制しなかった.アゾール系抗真菌薬は非アゾール系抗真菌薬より強力な抑制作用を示した.これらの抗真菌薬はJurkat T細胞においてIL-4, IL-5 promoter活性を抑制した.cAMPアナログは抗真菌薬のIL-4,IL-5産生抑制作用を解除した.抗CD3,CD28抗体刺激によりT細胞内のcAMP濃度は一過性に増加し,抗真菌薬はこのcAMPの増加を抑制した.アゾール系抗真菌薬はcAMPを産生するacenylate cyclaseを抑制し,非アゾール系抗真菌薬はcAMPを分解するcyclic nucleotide phosphodiesterase活性を増強した.抗真菌薬はcAMPシグナルの抑制を介してT細胞のIL-4,IL-5産生を抑制し,アトピー性皮膚炎患者のTh2偏位を是正すると考えられる.

DOI： 10.3314/jjmm.45.137

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

We examined in vitro effects of 17beta-estradiol on H2O2-induced apoptosis in human keratinocytes. 17beta-estradiol prevented the H2O2-induced apoptosis. H2O2 decreased, whereas 17beta-estradiol increased Bcl-2 protein and mRNA levels in keratinocytes, and H2O2 plus 17beta-estradiol led to basal levels. Overexpression of Bcl-2 protected keratinocytes against H2O2-induced apoptosis, indicating the anti-apoptotic effect of Bcl-2. H2O2 suppressed, whereas 17beta-estradiol enhanced bcl-2 promoter activity, and H2O2 plus 17beta-estradiol led to basal activity. Cyclic adenosine monophosphate (cAMP) response element on bcl-2 promoter was responsible for the effects of 17beta-estradiol and H2O2. Bcl-2 expression was enhanced by membrane-impermeable bovine serum albumin-conjugated 17beta-estradiol, indicating the effects via membrane 17beta-estradiol-binding sites. H2O2 decreased, whereas 17beta-estradiol increased the amount of phosphorylated cAMP response element-binding protein and cAMP response element-dependent transcriptional activity, and H2O2 plus 17beta-estradiol led to basal levels. H-89, an inhibitor of cAMP-dependent protein kinase A, suppressed basal and 17beta-estradiol-induced cAMP response element-binding protein phosphorylation, cAMP response element-dependent transcriptional activity, Bcl-2 expression, and apoptosis resistance. The cAMP analog, dibutyryl cAMP, enhanced cAMP response element-binding protein phosphorylation, cAMP response element-dependent transcriptional activity, Bcl-2 expression, and apoptosis resistance. 17beta-estradiol increased intracellular cAMP level and protein kinase A activity, whereas these were not altered by H2O2. Keratinocytes expressed mRNA for estrogen receptor beta and guanine nucleotide-binding protein-coupled receptor, GPR30. GPR30 anti-sense oligonucleotide did, but anti-sense estrogen receptor beta did not suppress 17beta-estradiol-induced cAMP signal, cAMP response element-binding protein phosphorylation, Bcl-2 expression, and apoptosis resistance. These results suggest that 17beta-estradiol may enhance Bcl-2 expression and prevent H2O2-induced apoptosis by phosphorylating cAMP response element-binding protein via cAMP/protein kinase A pathway in keratinocytes. These effects of 17beta-estradiol may be mediated via membrane GPR30.

DOI： 10.1111/j.1523-1747.2003.12617.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

We examined in vitro effects of 17beta-estradiol (E2) on nerve growth factor production by macrophages derived from monocytic cell line THP-1-or periphereal blood monocytes. E2 and membrane-impermeable bovine serum albumin-conjugated E2 (E2-BSA) enhanced nerve growth factor secretion and mRNA expression in both types of macrophages E2 enhanced nerve growth factor promotor activity in THP-1-derived macrophages and two activator protein-1 binding sites on the promoter were responsible for the enhancement. E2 and E2-BSA enhanced transcriptional activity and DNA binding of activator protein-1. E2 and E2-BSA shifted the activator protein-1 composition from c-Jun homodimers to c-Fos/c-jun heterodimers. E2 and E2-BSA transiently induced c-Fos mRNA, which was constitutively undetectable in both types of macrophages. Adenylate cyclase inhibitor SQ22536 suppressed E2-induced nerve growth factor production and c-Fos expression. E2 and E2-BSA increased intracellular cyclic adenosine monophosphate level in both types of macrophages. Antisense oligonucleotide against guanine nucleotide-binding protein-coupled receptor, GPR30 suppressed the E2-induced cyclic adenosine monophosphate signal, c-Fos expression, and nerve growth factor secretion in both types of macrophages. These results suggest that E2 may enhance nerve growth factor production by inducing c-Fos expression via cyclic adenosine monophosphate signal in macrophages. These effects may be mediated via GPR30.

DOI： 10.1046/j.1523-1747.2003.12487.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

A chemokine, monocyte chemoattractant protein 1 (MCP-1), attracts macrophages. The production of MCP-1 is enhanced in keratinocytes of psoriatic lesions, which may contribute to macrophage infiltration into the lesions. It is known that estrogen regulates the course of psoriasis. We examined in vitro effects of 17beta-estradiol (E2) on MCP-1 production by human keratinocytes. E2 inhibited constitutive and 12-O-tetradecanoylphorbol-13-acetate-induced MCP-1 secretion, mRNA expression, and promoter activity in keratinocytes, and these effects of E2 were counteracted by estrogen receptor antagonist ICI 182 780. GC-rich Sp1 element and activator protein 1 (AP-1) element on MCP-1 promoter were required for constitutive and 12-O-tetradecanoylphorbol-13-acetate-induced transcription, respectively, and involved in transrepression by E2. E2 inhibited constitutive Sp1 and 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 transcriptional activities whereas it did not inhibit DNA binding of Sp1 or AP-1 c-Fos/c-Jun. E2 inhibited Sp1 and AP-1 transcriptional activities and MCP-1 promoter activity in estrogen receptor beta (ERbeta) transfected SKBR3 cells. Deletion of the A/B region or mutation of activation function 2 in ERbeta abrogated E2-dependent transcriptional inhibition by ERbeta whereas mutation of DNA-binding domain retained the inhibitory effects. Transfection of ERbeta enhanced the inhibitory effects of E2 on Sp1 and AP-1 transcriptional activities and MCP-1 promoter activities in nontransfected keratinocytes. Coimmunoprecipitation studies showed an E2-dependent association of ERbeta with Sp1 or AP-1 in ERbeta-transfected keratinocytes. These results suggest that E2-bound ERbeta may inhibit MCP-1 gene expression by inhibiting Sp1 and AP-1 transcriptional activities in keratinocytes. A/B region and intact activation function 2 of ERbeta may be responsible for the effects of E2.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

A chemokine, regulated upon activation, normal T cell expressed and secreted (RANTES) attracts T helper-1 cells and macrophages. The production of RANTES is enhanced in keratinocytes of psoriatic skin lesions, which may contribute to the inflammatory infiltrate. It is known that estrogen regulates the natural course of psoriasis. We examined the in vitro effects of 17beta-estradiol on RANTES production by human keratinocytes. 17beta-estradiol inhibited tumor necrosis factor-alpha or interleukin-1beta-induced RANTES secretion, mRNA expression, and promoter activity in keratinocytes, and these effects of 17beta-estradiol were counteracted by estrogen receptor antagonist ICI 182 780. Two nuclear factor kappaB elements on RANTES promoter were required for tumor necrosis factor-alpha or interleukin-1beta-induced transcription and involved in the inhibition by 17beta-estradiol. 17beta-estradiol inhibited nuclear factor kappaB transcriptional activity, whereas it did not inhibit DNA binding of nuclear factor kappaB or phosphorylation or degradation of the inhibitor of nuclear factor kappaB alpha in tumor necrosis factor-alpha or interleukin-1beta-stimulated keratinocytes. 17beta-estradiol-induced inhibition of nuclear factor kappaB transcriptional activity and RANTES promoter activity was rescued by overexpression of a coactivator cyclic AMP response element-binding protein (CREB) or nuclear factor kappaB p65 but not by steroid receptor coactivator-1 or nuclear factor kappaB p50. The overexpression of CREB-binding protein rescued 17beta-estradiol-induced inhibition of transcription mediated by a chimeric protein, GAL4-p65(286-551), which contained GAL4 DNA binding domain fused to C-terminal transactivating domain of p65 (amino acids 286-551). The transfection of estrogen receptor alpha or estrogen receptor beta into estrogen receptor-negative SKBR3 cells resulted in 17beta-estradiol-mediated inhibition of transcription via GAL4-p65(286-551). These results suggest that 17beta-estradiol-bound estrogen receptor may inhibit nuclear factor kappaB-dependent transcription of RANTES gene by competing with p65 for limiting amounts of CREB-binding protein.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

The natural course of psoriasis is often modulated during pregnancy, indicating the regulatory effect of estrogen or progesterone on psoriasis. Interferon-induced protein of 10 kDa chemoattracts T helper 1 cells, and interferon-induced protein of 10 kDa production by keratinocytes is enhanced in psoriatic skin lesions. We examined in vitro effects of sex hormones on the interferon-induced protein of 10 kDa production by human keratinocytes. 17beta-estradiol inhibited interferon-gamma-induced interferon-induced protein of 10 kDa secretion, mRNA expression, and promoter activity. Interferon-stimulated response element on the promoter was responsible for the inhibition by 17beta-estradiol. Interferon-gamma-induced protein of 10 kDa production was also inhibited by anti-estrogens, ICI 182 780 and tamoxifen, and membrane-impermeable bovine serum albumin-conjugated 17beta-estradiol, suggesting the effects via membrane estrogen receptor, whereas 17alpha-estradiol, progesterone, and dihydrotestosterone had no effects. 17alpha-estradiol and bovine serum albumin-conjugated 17beta-estradiol suppressed interferon-gamma-induced transcription through the interferon-stimulated response element and signal transducer and activator of transcription 1alpha binding to interferon-stimulated response element. 17beta-estradiol and bovine serum albumin-conjugated 17beta-estradiol suppressed interferon-gamma-induced tyrosine phosphorylation of signal transducer and activator of transcription lot, and Janus tyrosine kinase 1 and 2. 17beta-estradiol-mediated suppression on the interferon-gamma-induced signal transducer and activator of transcription 1alpha activation and interferon-induced protein of 10 kDa synthesis was counteracted by adenylate cyclase inhibitor SQ22536. 17beta-estradiol, bovine serum albumin-conjugated 17beta-estradiol, ICI 182 780, and tamoxifen increased intracellular 3',5'-adenosine cyclic monophosphate level by activating adenylate cyclase in keratinocytes. Fluorescein isothiocyanate-labeled bovine serum albumin-conjugated 17beta-estradiol bound to the surface of keratinocytes, and mRNA for estrogen receptor beta but not for estrogen receptor alpha was detected in keratinocytes. These results suggest that 17beta-estradiol may interact with the membrane receptor on keratinocytes and generate 3',5'-adenosine cyclic monophosphate by activating adenylate cyclase, which may lead to the inhibition of interferon-gamma-induced signal transducer and activator of transcription la activation and interferon-induced protein of 10 kDa synthesis.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

A neuropeptide substance P is related to skin inflammation. Interferon-induced protein of 10 kDa (IP-10) chemoattracts T helper 1 cells, and interferon-induced protein of 10 kDa production by keratinocytes is enhanced in inflammatory skin diseases such as psoriasis. We examined the in vitro effects of substance P on interferon-induced protein of 10 kDa production by human keratinocytes. Though substance P alone did not induce interferon-induced protein of 10 kDa production, it enhanced interferon-induced protein of 10 kDa secretion, mRNA expression, and promoter activity induced by suboptimal concentrations of interferon-gamma. Interferon-stimulated response element and two nuclear factor-kappaB sites on interferon-induced protein of 10 kDa promoter were responsible for the enhancement by substance P. Substance P alone enhanced transcriptional activity and transcription factor binding through the two nuclear factor-kappaB sites, whereas it did not alter interferon-gamma-induced transcriptional activity and transcription factor binding through interferon-stimulated response element. The effects of substance P on interferon-induced protein of 10 kDa production and nuclear factor-kappaB activation were inhibited by neurokinin-1 receptor antagonist, phospholipase C inhibitor, intracellular Ca2+ chelator, and anti-oxidant. These results suggest that substance P may induce nuclear factor-kappaB activation and interferon-induced protein of 10 kDa production in synergy with interferon-gamma via neurokinin-1 receptor on keratinocytes. These effects of substance P may be mediated via phospholipase C activation, intra-cellular Ca2+ signal, and reactive oxygen intermediates.

DOI： 10.1046/j.1523-1747.2002.19626.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

Interferon-induced protein of (IP-10) inhibits tumor progression. Tumor cells can produce interferon-induced protein of IP-10 in response to interferon-gamma. Histamine in the vicinity of tumor cells may sustain the tumor progression. We examined the in vitro effects of histamine on interferon-induced protein of IP-10 production in human squamous cell carcinoma and melanoma. Histamine suppressed interferon-gamma-mediated interferon-induced protein of IP-10 secretion and mRNA expression in SV40-transformed keratinocytes, SCC15, SCC4, and melanoma WM115, WM266-4, and C32. Histamine suppressed interferon-gamma-induced interferon-mediated protein of IP-10 promoter activation in these cells, and the interferon-stimulated response element on the promoter was responsible for the suppression. Histamine suppressed interferon-gamma-mediated transcription through the interferon-stimulated response element and signal transducer and activator of transcription 1alpha binding to the interferon-stimulated response element. Histamine suppressed interferon-gamma-induced tyrosine phosphorylation of the signal transducer and activator of transcription 1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. Histamine-mediated suppression on the interferon-gamma-induced interferon-mediated protein of IP-10 synthesis was counteracted by the H2 receptor antagonist cimetidine, adenylate cyclase inhibitor SQ22536, and protein kinase A inhibitor H-89, but were not affected by H1 receptor antagonist mepyramine. Cimetidine, SQ22536, and H-89 also counteracted histamine-mediated suppression on the interferon-gamma-induced transcription through the interferon-stimulated response element, signal transducer and activator of transcription 1alpha binding to the interferon-stimulated response element, and tyrosine phosphorylation of the signal transducer and activator of transcription 1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. Histamine increased intracellular 3',5'-adenosine cyclic monophosphate level and protein kinase A activity in squamous cell carcinoma and melanoma, and the effects of histamine were blocked by cimetidine. These results suggest that histamine may interact with H2 receptor on squamous cell carcinoma and melanoma and generate 3',5'-adenosine cyclic monophosphate, which may activate protein kinase A. The cyclic 3',5'-adenosine monophosphate/protein kinase A signaling pathway induced by histamine may inhibit interferon-g-induced signal transducer and activator of transcription 1alpha activation and suppress interferon-induced protein of IP-10 synthesis.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

Interferon-induced protein of 10 kDa (IP-10) induces antitumor immunity. Cyclooxygenase-2 and its metabolite prostaglandin E2 (PGE(2)) are overexpressed in tumor cells, which may suppress antitumor immunity. We examined the in vitro effects of cyclooxygenase-2 inhibitor NS398 on IP-10 production in human epidermoid carcinoma A431. NS398 enhanced interferon-c-induced IP-10 secretion, mRNA expression, and promoter activation in A431, and exogenous PGE(2) antagonized the enhancement. Interferon-stimulated response element (ISRE) on IP-10 promoter was responsible for the transcriptional regulation by NS398 and PGE(2). NS398 enhanced interferon-gamma-induced transcription through ISRE and binding of signal transducer and activator of transcription 1alpha (STAT1alpha to ISRE in A431, and PGE(2) antagonized the enhancement. NS398 enhanced interferon-gamma-induced tyrosine phosphorylation of STAT1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2, and PGE(2) antagonized the enhancement. PGE(2)-mediated suppression of IP-10 synthesis was counteracted by adenylate cyclase inhibitor SQ22536 and protein kinase A inhibitor H-89, and PGE(2) receptor EP4 antagonist AH23848B. AH23848B, SQ22536, and H-89 counteracted the PGE(2)-mediated suppression of ISRE-dependent transcription, STAT1alpha binding to ISRE, and tyrosine phosphorylation of STAT1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. PGE(2) increased intracellular cAMP level and protein kinase A activity in A431 pretreated with NS398, and AH23848B blocked the effects of PGE(2). These results suggest that A431-derived PGE(2) may generate cAMP signal via EP4 in A431, which may activate protein kinase A, and may resultantly inhibit interferon-gamma-induced STAT1alpha activation and IP-10 synthesis. The results also suggest that NS398 may restore IP-10 synthesis by preventing PGE(2) production in A431 and thus may be therapeutically useful for skin cancer.

DOI： 10.1046/j.1523-1747.2002.19510.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

We previously reported that antimycotic agent ketoconazole suppressed interleukin-4 production in T cells from patients with atopic dermatitis. We herein studied if ketoconazole may suppress B cell IgE class switching. Interleukin-4 plus anti-CD40-induced IgE secretion was enhanced in peripheral blood surface IgE- B cells from atopic dermatitis patients compared to those from normal donors, and the secretion was inhibited by ketoconazole. Ketoconazole suppressed interleukin-4 plus anti-CD40-induced germline and mature epsilon transcripts in surface IgE-B cells. Ketoconazole also inhibited interleukin-4 plus anti-CD40-induced activation of germline epsilon promoter in human Burkitt lymphoma Ramos cells. The regions -171/-155 by containing CCAAT/ enhancer-binding protein element and -155/-109 by containing Stat6 and nuclear factor kappaB elements were required for the ketoconazole-induced inhibition of the germline epsilon promoter activity. Ketoconazole inhibited interleukin-4 plus anti-CD40-induced enhancer activities of CCAAT/enhancer-binding protein and nuclear factor kappaB, and those of composite elements of CCAAT/enhancer-binding protein/Stat6 or of Stat6/nuclear factor kappaB, but did not alter that of Stat6 in Ramos cells. cAMP analog reversed the inhibitory effects of ketoconazole on interleukin-4 plus anti-CD40-induced IgE secretion, germline and mature epsilon transcripts, and epsilon germline promoter activation. Interleukin-4 plus anti-CD40 increased intracellular CAMP by activating cAMP-synthesizing adenylate cyclase in surface IgE- B cells, and the increase was greater in the cells from atopic dermatitis patients than in those from normal donors. Ketoconazole suppressed interleukin-4 plus anti-CD40-induced activation of adenylate cyclase in surface IgE- B cells. These results suggest that ketoconazole may suppress interleukin-4 plus anti-CD40-induced B cell IgE class switching by inhibiting cAMP signal, and stress its prophylactic effects on allergic diseases.

DOI： 10.1046/j.1523-1747.2002.01864.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING LTD  

Background It is suggested that skin fungi may be involved in the development of atopic dermatitis (AD) and psoriasis vulgaris (PV).
Objective We studied skin fungus-induced Th1- or Th2-related cytokine, chemokine and prostaglandin E-2 (PGE (2) ) secretion in peripheral blood mononuclear cells (PBMC) from patients with AD and PV and normal subjects.
Methods PBMC were cultured with the extracts of Malassezia furfur (MF), Candida albicans (CA) and Trichophyton rubrum (TR). The cytokine, chemokine and PGE(2) amounts in the supernatants were measured by enzyme-linked immunosorbent assays.
Results MF induced IL-4 and macrophage-derived chemokine (MDC) secretion in AD patients, while induced IFN-gamma and interferon-inducible protein of 10 kDa (IP-10) secretion in PV patients, however, did not induce either secretion in normal subjects. CA induced IL-4, MDC, IFN-gamma and IP-10 secretion in AD and PV patients and normal subjects. In AD patients, the magnitude of IL-4 and MDC responses to CA was higher than that to MF. Compared with PV patients and normal subjects, the magnitude of IL-4 and MDC responses to CA was higher while that of IFN-gamma and IP-10 responses to CA was lower in AD patients. TR induced moderate IL-4 and MDC secretion only in AD patients. The three fungi induced higher levels of PGE (2) secretion in AD patients than in PV patients and normal subjects. Cyclooxygenase-2 inhibitor NS-398 suppressed PGE(2) responses to MF, CA and TR, and partially suppressed IL-4 and MDC responses to MF, CA and TR, while enhanced IFN-gamma and IP-10 responses to CA in AD patients, and these effects of NS-398 were reversed by cyclic AMP analogue.
Conclusion AD patients manifest Th2-skewed responses to MF, CA and TR, which may be partially attributable to the enhanced PGE(2) responses to these fungi. PV patients manifest Th1-skewed responses to MF.

DOI： 10.1046/j.1365-2745.2002.01459.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

Cyclooxygenase-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The overexpression of cyclooxygenase-2 has been reported in skin cancer cells, and may be involved in carcinogenesis. Prostaglandin E-2 , the end product of cyclooxygenase-2-induced catalysis, autoamplifies the cyclooxygenase-2 expression. It is suggested that an anti-mycotic drug, ketoconazole may inhibit carcinogenesis. We herein investigated if ketoconazole may inhibit prostaglandin E-2 -induced cyclooxygenase-2 expression in human epidermoid carcinoma A-431 cells. Ketoconazole suppressed prostaglandin E-2 -induced cyclooxygenase-2 protein and mRNA expression and promoter activation in A-431; the suppressive effects of ketoconazole were counteracted by cyclic adenosine monophosphate analog. Analyses using deleted or mutated cyclooxygenase-2 promoters revealed that cyclic adenosine monophosphate response element (- 59 to - 53 bp) on the promoter was involved in prostaglandin E-2 -induced stimulation and ketoconazole-induced inhibition of the promoter activity. Electrophoretic mobility shift assays indicated that cyclic adenosine monophosphate response element binding protein and activating transcription factor-1 may constitutively bind to cyclic adenosine monophosphate response element on cyclooxygenase-2 promoter. Prostaglandin E-2 increased the proportion of phosphorylated forms among total bound cyclic adenosine monophosphate response element binding protein/activating transcription factor-1, and the effect was suppressed by ketoconazole. Prostaglandin E-2 induced the phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor-1, and the phosphorylation was suppressed by cyclic adenosine monophosphate-dependent protein kinase (protein kinase A) inhibitor, indicating protein kinase A-mediated phosphorylation. Ketoconazole suppressed the prostaglandin E-2 -induced phosphorylation of cyclic adenosine monophosphate response element binding protein/activating transcription factor-1. Prostaglandin E-2 increased intracellular cyclic adenosine monophosphate level by activating adenylate cyclase in A-431, and the increase was suppressed by ketoconazole. These results suggest that ketoconazole may suppress prostaglandin E-2 -induced cyclooxygenase-2 expression by inhibiting the cyclic adenosine monophosphate signal in A-431, and stress its anti-cancer effect.

DOI： 10.1046/j.1523-1747.2002.01804.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

We studied the in vitro effects of sex hormones on vascular endothelial growth factor (VEGF) production in differentiated THP-1 monocytic cells. Phorbol-12-myristate-13-acetate differentiated THP-1 into macrophage-like cells. 17beta-estradiol (10(-9) M) increased VEGF secretion of controls 3.1-fold in differentiated THP-1 and this effect of 17beta-estradiol was antagonized by dihydrotestosterone, although dihydrotestosterone alone did not alter VEGF secretion. 17beta-estradiol increased steady-state mRNA level of VEGF and the increase was counteracted by dihydrotestosterone in differentiated THP-1, although dihydrotestosterone alone did not alter the VEGF mRNA level. Progesterone did not affect the constitutive and 17beta-estradiol-induced VEGF secretion and mRNA level. Transient transfection revealed that 17beta-estradiol enhanced chloramphenicol acetyl transferase expression driven by VEGF promoter and the enhancement was antagonized by dihydrotestosterone. Adenylate cyclase inhibitor suppressed 17beta-estradiol-induced enhancement of VEGF secretion, mRNA level, and promoter activity, whereas dihydrotestosterone-induced suppression on the effects of 17beta-estradiol was counteracted by 3',5'-adenosine cyclic monophosphate (CAMP) analog. 17beta-estradiol increased intracellular cAMP level by activating adenylate cyclase, while dihydrotestosterone reduced the basal and 17beta-estradiol-increased cAMP level by inhibiting adenylate cyclase. Transfection with 5'-deleted VEGF promoters demonstrated that the region between -88 and -66 by may be involved in the transcriptional regulation by each hormone. The mutation within activator protein-2 element in this region abrogated the transcriptional stimulation and repression by the respective hormones. 17beta-estradiol activated transcription from activator protein-2-responsive reporter plasmid while dihydrotestosterone antagonized the effect of 17beta-estradiol. These results suggest that 17beta-estradiol enhances VEGF production while dihydrotestosterone antagonizes the effect of 17beta-estradiol via up- or downregulation of adenylate cyclase in differentiated THP-1.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

It is reported that anti-mycotic agents are effective for the treatment of patients with atopic dermatitis. We studied the in vitro effects of anti-mycotics on T helper-1 and T helper-2 cytokine production in anti-CD3 plus anti-CD28-stimulated T cells from atopic dermatitis patients and normal donors. The amounts of interleukin-4 and interleukin-5 secreted by anti-CD3/CD28-stimulated T cells were higher in atopic dermatitis patients than in normal donors. Azole derivatives, ketoconazole, itraconazole, miconazole, and nonazole terbinafine hydrochloride, and tolnaftate reduced interleukin-4 and interleukin-5 secretion without altering that of interferon-gamma and interleukin-2 in anti-CD3/CD28-stimulated T cells from both atopic dermatitis patients and normal donors. The azole derivatives were more inhibitory than nonazole anti-mycotics. These anti-mycotics reduced the anti-CD3/CD28-induced mRNA expression and promoter activities for interleukin-4 and interleukin-5. The 3',5'-cyclic adenosine monophosphate analog dibutyryl 3',5'-cyclic adenosine monophosphate reversed the inhibitory effects of the anti-mycotics on interleukin-4 and interleukin-5 secretion, mRNA expression, and promoter activities. Anti-CD3/CD28 transiently (less than or equal to5 min) increased intracellular 3',5'-cyclic adenosine monophosphate in T cells, and the increase was greater in atopic dermatitis patients than in normal donors. The increase of 3',5'-cyclic adenosine monophosphate by anti-CD3/CD28 correlated with interleukin-4 and interleukin-5 secretion by anti-CD3/CD28. The transient 3',5'-cyclic adenosine monophosphate increase was suppressed by anti-mycotics, and azole derivatives were more suppressive than nonazoles. Azole derivatives inhibited the activity of cyclic adenosine monophosphate-synthesizing adenylate cyclase whereas terbinafine hydrochloride and tolnaftate enhanced the activity of 3',5'-cyclic adenosine monophosphate-hydrolyzing cyclic nucleotide phosphodiesterase in atopic dermatitis and normal T cells. These results suggest that the anti-mycotics may suppress interleukin-4 and interleukin-5 production by reducing 3',5'-cyclic adenosine monophosphate signal, and stress their potential use for the suppression of T helper-2-mediated allergic reactions.

DOI： 10.1046/j.0022-202x.2001.01566.x

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Dermatological Association  

SLEは多彩な皮膚症状，臓器症状，異常検査所見を呈する全身性自己免疫疾患である．皮膚症状にはLEに特異的な皮疹と，LEに特異的ではないが多くの膠原病に共通して出現する非特異的皮膚症状があり，皮膚病変の解析は，SLEの早期診断や予後の判定に有用である．SLE患者血清には抗DNA抗体，抗U1 RNP抗体，抗Sm抗体，抗SS-A抗体，抗SS-B抗体など多種の自己抗体が検出され，あるものは臨床症状と相関し，予後判定の指標となる．近年，自己抗体に対応する自己抗原が明らかにされてきている．SLEの発症には，T，B細胞両系にわたる自己抗原に対するトレランスの破綻やサイトカイン系の異常が関与している．SLEの治療に際しては，患者の病態を的確に把握し，副腎皮質ホルモンなどの免疫抑制剤の全身投与が必要な症例を見極めることが大切である．抗リン脂質抗体症候群はSLEに合併することがあり，抗凝固療法の併用を要する．

DOI： 10.14924/dermatol.111.1471

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その他リンク： https://jlc.jst.go.jp/DN/JALC/00152374554?from=CiNii

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE INC  

We studied the effects of 17 beta -estradiol, progesterone, and dihydrotestosterone on in vitro growth of human metastatic melanoma. Each sex hormone inhibited the growth of melanoma receptor-dependently; 17 beta -estradiol inhibited H-3-thymidine uptake of estrogen receptor-positive WM266-4 and NM26, but not that of the receptor-negative HS15. Progesterone inhibited H-3-thymidine uptake of progesterone receptor-positive WM266-4 and HS15, but not that of the receptor-negative NM26. Dihydrotestosterone inhibited H-3-thymidine uptake of androgen receptor-positive HS15 and NM26, but not that of the receptor-negative WM266-4. The growth inhibition by each hormone was counteracted by the respective hormone receptor antagonist. The combination of more than two hormones neither gave additive nor synergistic growth inhibition. The growth inhibition by each sex hormone was counteracted by interleukin-8 but not by the other growth factors. Each sex hormone reduced the constitutive interleukin-8 secretion and mRNA levels in the respective receptor-positive melanoma but not in the receptor-negative melanoma. Transient transfection showed that each sex hormone inhibited the constitutive chloramphenicol acetyltransferase expression driven by interleukin-8 promoter in the respective receptor-positive melanoma but not in the receptor-negative melanoma. Transfection with a series of 5'-deleted interleukin-8 promoter/chloramphenicol acetyltransferase reporter constructs demonstrated that the sequences between -98 and -63 by on interleukin-8 promoter may be involved in the transcriptional repression. These data suggest that 17 beta -estradiol, progesterone, and dihydrotestosterone suppress the growth of melanoma by inhibiting interleukin-8 production in a receptor-dependent manner.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

We studied the activities of 3 ' ,5 ' -adenosine-cyclic monophosphate (cAMP)- synthesizing adenylate cyclase (AC) and cAMP-hydrolyzing cyclic nucleotide phosphodiesterase (PDE) in phytohemagglutinin (PHA)- or anti-CD3 plus anti-CD28-stimulated human T cells, and examined their roles in interleukin-13 (IL-13) production. The AC inhibitor MDL 12,330A [cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine hydrochloride] completely blocked PHA or anti-CD3/CD28-induced IL-13 production. The PDE 1 inhibitor 8-methoxymethyl-3-isobutyl-1-methylxanthine or the PDE4 inhibitor rolipram partially inhibited IL-13 production, and the addition of both resulted in 100 or 85% inhibition in PHA- or anti-CD3/CD28-stimulated T cells, respectively. AC in T cells was transiently activated 5 min after stimuli, followed by the transient activation of PDE4 at 30 min. PDE1 activity, undetectable in resting T cells, was detected 3 hr after stimuli, and then increased gradually. Although PDE1-, 2-, 3-, and 4-independent PDE activity was low (less than or equal to 15% of total), it began to increase 3 hr after anti-CD3/CD28; the increase was blocked by PDE7 antisense oligonucleotide, and such an increase was not induced by PHA. PHA or anti-CD3/CD28 induced PDE IB mRNA expression, undetectable in resting T cells. PDE4 mRNA level in T cells was not altered by either stimulus. PDE7 mRNA expression was detected in resting T cells, and was enhanced by anti-CD3/CD28, but not by PHA. The cAMP level of T cells increased 5 min after stimuli, returned to the basal level at 2 hr, and then continued to decrease. These results suggest that PHA or anti-CD3/CD28 initially (less than or equal to5 min) increases cAMP in T cells via AC, then reverses the increase via PDE4 (less than or equal to2 hr), and in the later phase (&gt;2 hr) further decreases cAMP via PDEI. Both the time-dependent increase and decrease of cAMP may be required for IL-13 production. (C) 2001 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0006-2952(01)00688-8

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE INC  

We studied the effects of various gangliosides on in vitro growth of human metastatic melanoma WM266-4. GD1b, GT1b, and GQ1b inhibited H-3-thymidine uptake and growth rate of WM266-4 whereas the other gangliosides were ineffective. The growth inhibition by GD1b, GT1b, and GQ1b was counteracted by interleukin-8 but not by the other growth factors. The growth inhibition by gangliosides was not detected in the presence of anti-interleukin-8 antibody. GD1b, GT1b, and GQ1b reduced the constitutive interleukin-8 secretion and mRNA levels in WM266-4. Transient transfection showed that GD1b, GT1b, and GQ1b inhibited the constitutive chloramphenicol acetyltransferase expression driven by interleukin-8 promoter in WM266-4. Transfection with a series of 5'-deleted mutants demonstrated that the sequences between -98 and -62 by on interleukin-8 promoter may be involved in the transcriptional repression by these gangliosides. Cyclic AMP analog dibutyryl cAMP counteracted GD1b, GT1b, and GQ1b-induced inhibition of interleukin-8 production at the levels of protein secretion, mRNA expression, and promoter activity. GD1b, GT1b, and GQ1b reduced cAMP level and protein kinase A activity in WM266-4. These gangliosides suppressed adenylate cyclase activity without altering that of cyclic nucleotide phosphodiesterase in WM266-4. The data indicate that GD1b, GT1b, and GQ1b may suppress the growth of melanoma by inhibiting interleukin-8 production via the inhibition of adenylate cyclase.

DOI： 10.1046/j.0022-202X.2001.01423.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE INC  

We studied the relationship between cAMP and house dust mite-induced cytokine production in T cells from mite-sensitive patients with atopic dermatitis, T cells from atopic dermatitis patients secreted high level of interleukin-13 (mean 851.1 pg per ml) when cultured with autologous monocytes pulsed with Dermatophagoides pteronyssinus extract. Dermatophagoides pteronyssinus-induced interleukin-13 secretion was not detected in normal subjects. Adenylate cyclase inhibitor MDI, 12,330A and cyclic nucleotide phosphodiesterase type 4 inhibitor rolipram blocked Dermatophagoides pteronyssinus-induced interleukin-13 secretion in atopic dermatitis T cells, In atopic dermatitis T cells, cAMP level rose at 5 min after Dermatophagoides pteronyssinus stimulus then decreased to the basal level at 1 h. MDL 12,330A blocked the Dermatophagoides pteronyssinus-induced cAMP elevation while rolipram blocked its reversal. In atopic dermatitis T cells, adenylate cyclase activity increased at 5 min after Dermatophagoides pteronyssinus stimulus, followed by the increase of cyclic nucleotide phosphodiesterase activity at 15 min. In atopic dermatitis T cells, phospholipase C inhibitor ET-18-OCH3 blocked Dermatophagoides pteronyssinus-induced activation of adenylate cyclase, while rolipram, protein kinase A inhibitor H-89, and MDL 12,330A blocked the activation of cyclic nucleotide phosphodiesterase, These results suggest that Dermatophagoides pteronyssinus may first increase cAMP in atopic dermatitis T cells by activating adenylate cyclase via phospholipase C, and next decrease cAMP by activating cyclic nucleotide phosphodiesterase 4 via protein kinase A, which may be activated by adenylate cyclase-generated cAMP signal. These events are required for interleukin-13 response Dermatophagoides pteronyssinus.

DOI： 10.1046/j.1523-1747.2001.01196.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Objective. We previously reported that ganglioside GD1a greatly enhanced spontaneous immunoglobulin (Ig) production by human peripheral blood mononuclear cells (PBMC) in vitro. We herein examined the mechanism for the stimulatory effect of GD1a.
Materials and Methods. PBMC from healthy volunteers were cultured with GD1a. The amounts of IgG, IgM, and IgA and cytokine activity in the culture supernatants were measured by enzyme-linked immunosorbent assays. Proliferation was determined by [H-3] thymidine uptake.
Results. GD1a at 10(-6) M increased IgG, IgM, and IgA production by PBMC 2.10-fold, 2.10-fold, and 2.23-fold above the control values, respectively. GD1a did not affect the proliferation and viability of PBMC. GD1a did not alter Ig production of B cells alone. Anti-interleukin-6 (IL-6) or anti-IL-10 antibody each partially blocked the GD1a-induced enhancement of Ig production by PBMC, and the addition of both antibodies completely blocked the enhancement. GD1a increased IL-6 and IL-10 production of monocytes without altering those of T cells or B cells. The supernatant from GD1a-treated monocytes enhanced B cell Ig production to a greater extent than that from medium-treated monocytes, The supernatant-mediated effect of GD1a was partially blocked by anti-IL-6 or anti-IL-10 antibody, and the addition of both antibodies completely blocked the GD1a effect. GD1a-induced increases of IL-6 and IL-10 production in monocytes were both blocked by Ca2+/calmodulin (CaM)-dependent phosphodiesterase (PDE) inhibitors, 8-methoxymethyl-3-isobutyl-1-methylxanthine and vinpocetin, but not by other signal-transducing enzyme inhibitors. The culture with GD1a enhanced Ca2+/CaM-dependent PDE activity in monocytes.
Conclusion. These results suggest that GD1a may indirectly enhance B cell Ig production in whole PBMC by increasing IL-6 and IL-10 production of monocytes via promoting Ca2+/ CaM-dependent PDE activity. (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc.

DOI： 10.1016/S0301-472X(00)00167-3

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Gangliosides are sialic acid-containing glycolipids, that have various immunomodulatory effects. We previously reported that various gangliosides in vitro either inhibited or enhanced spontaneous immunoglobulin (Ig) production by human peripheral blood mononuclear cells (PBMC). GD1b was one of the inhibitory gangliosides, In this study. we further examined the mechanism for the inhibitory effect of GD1b, The inhibitory effect of GD1b was revealed at 0.1 mu M, increased dose dependently, and was maximized at 10 mu M, which reduced spontaneous IgG, IgM, and IgA production of human PBMC by 50.5%, 52.0%, and 48.3% compared with controls, respectively. GD1b did not affect the proliferation and viability of PBMC, GD1b did not alter Ig production of B cells alone, Interleukin 6 (IL-6) and IL-10 each partially reversed the GD1b-induced inhibition of Ig production by PBMC, and the addition of both cytokines completely reversed the inhibition. When endogenous IL-6 and IL-10 were neutralized by specific antibodies, GD1b did not reveal inhibitory effects on the Ig production. GD1b inhibited IL-6 and IL-IO production of CD4(+) T cells, without affecting those of CD8(+) T cells, monocytes, or B cells, When CD4(+) T cells were preincubated with GD1b and washed and cultured with B cells and monocytes, Ig production was also suppressed. These results suggest that GD1b may indirectly suppress Ig production of B cells in whole PBMC by reducing IL-6 and IL-10 production of CD4(+) T cells, GD1b mag act as an important inhibitor of human humoral immune responses, (C) 1999 International Society for Published by Elsevier Science Inc.

DOI： 10.1016/S0301-472X(99)00093-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER MEDICAL ASSOC  

Objectives: To investigate the prevalence of anti-alpha-fodrin antibody in patients with Sjogren syndrome (SS), lupus erythematosus (LE), or both and the association of this antibody with other clinical manifestations.
Design: A study of screening and diagnostic tests. Mean follow-up was 152 months (range, 4-572 months).
Setting: A university hospital associated with a research laboratory in Tokyo,Japan.
Patients: Nine patients with primary SS, 15 patients with SS secondary to LE, and 44 patients with LE alone.
Main Outcome Measures: Frequencies of clinical and laboratory findings, including anti-alpha-fodrin antibody.
Results: Anti-alpha-fodrin antibody was more commonly detected in patients with primary (7/9; P&lt;.001) and secondary (9/15; P&lt;.001) SS than in those with LE alone (3/44). When patients with primary and secondary SS were combined and compared with those with LE alone, the sensitivity of anti-alpha-fodrin antibody was 67%, specificity was 93%, and both positive and negative predictive values were 84%. The presence of anti-alpha-fodrin antibody was associated with pernio, hyperglobulinemia, rheumatoid factor positivity, and the presence of anti-SS-B (La) antibody (P&lt;.01) but not with annular erythema, photosensitivity, vasculitis, or renal disorder.
Conclusions: Although anti-alpha-fodrin antibody was detected in patients with SS and in those with LE, it seemed to be more valuable for the diagnosis of SS than was anti-SS-A (Ro) because anti-alpha-fodrin was much less prevalent in patients with LE alone. It may be possible to consider this novel autoantibody as pathophysiologically associated with some extraglandular manifestations characteristically seen in patients with SS.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE LTD  

Gangliosides are sialic acid-containing glycolipids and have various immunomodulatory effects. We previously reported that various gangliosides in,vitro either inhibited or enhanced spontaneous immunoglobulin production by human peripheral blood mononuclear cells (PBMC). Among them, GTlb was the most inhibitory. In this study, we further examined the mechanism for the inhibitory effect of CTlb. The inhibitory effect of GTlb was apparent at 0.1 mu M, increased dose dependently, and was maximal at 10 mu M. In the presence of 10 mu M CTlb, spontaneous production of immunoglobulin (Ig)G, IgM and IgA in human PBMC was reduced by 60%, 59.5% and 58%, respectively, compared with controls. GTlb did not affect the proliferation and viability of PBMC, and did not enhance their apoptosis. GTlb did not alter immunoglobulin production of B cells alone. Interleukin (IL)-6 and IL-10 each partially reversed the GTlb-induced inhibition of immunoglobulin production by PBMC, and the presence of both cytokines completely reversed the inhibition. GTlb inhibited IL-6 and IL-IO production in monocytes, without affecting that in T or B cells. When monocytes were preincubated with GTlb, washed and then cultured with B and T cells, the immunoglobulin production was also suppressed. These results suggest that GTlb may indirectly suppress immunoglobulin production of B cells in whole PBMC via reducing the production of IL-6 and IL-10 in monocytes. It is thus indicated that GTlb may act as an important inhibitor for human humoral immune responses.

DOI： 10.1046/j.1365-2567.1999.00734.x

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC  

Gangliosides are sialic acid-containing glycosphingolipids and exhibit various physiologic functions. Gangliosides GD1a and GM3 strongly induced interleukin-10 (IL-10) protein secretion and mRNA expression in T cells from normal human subjects while the other gangliosides were ineffective. IL-10 induction by both gangliosides was completely blocked by protein tyrosine kinase (PTK) inhibitors, herbimycin A, genistein, and tyrphostin AG 1288, but not by other signal transduction inhibitors. These results suggest that GD1a and GM3 may induce IL-10 production in T cells by regulating the PTK-dependent signaling pathway. These gangliosides may thus act as important immunoregulators via IL-10. (C) 1999 Academic Press.

DOI： 10.1006/bbrc.1999.0281

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective. To study the in vitro effect of estrogen on IgG anti-double-stranded DNA (anti-dsDNA) antibody and total IgG production in peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE), in order to elucidate its regulatory role in SLE.
Methods. PBMC from SLE patients and normal donors were cultured with 17 beta-estradiol (E-2). IgG anti-dsDNA antibodies, total IgG, and cytokine activity in the culture supernatants were measured by enzyme-linked immunosorbent assay.
Results, E-2 enhanced production of IgG anti-dsDNA antibodies as well as total IgG in PBMC from SLE patients. Anti-dsDNA production in patients with inactive disease was less responsive to E-2 than that in patients with active disease. E-2 also enhanced total IgG, but not anti-dsDNA, production in the PBMC of normal donors. Antibody production was increased by E-2 to a lesser extent in patients' B cells than in their PBMC. Anti-interleukin-10 (anti-IL-10) antibodies partially blocked the E-2-induced increase in antibody production in patients' PBMC, but anti-IL-10 had no effect on B cells, E-2 increased IL-10 production by patients' monocytes, Exogenous IL-10 acted additively with E-2 in increasing antibody production in patients' B cells.
Conclusion. These results suggest that E-2 may polyclonally increase the production of IgG, including IgG anti-dsDNA, in SLE patients' PBMC by enhancing B cell activity and by promoting IL-10 production in monocytes, These findings support the involvement of E-2 in the pathogenesis of SLE.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MUNKSGAARD INT PUBL LTD  

Cutaneous lupus mucinosis (CLM) is a rare variant of lupus erythematosus eruptions. Our 5 cases with CLM were reviewed. All were men with systemic lupus erythematosus (SLE). CLM occurred as asymptomatic cutaneous papules, nodules, or plaques on the trunk, upper and lower extremities, and face. Histopathol ogy of CLM mainly revealed abundant mucin deposits among splayed collagen bundles throughout the dermis. However, some CLM lesions showed discoid lupus erythematosus-like epidermal and dermal changes and/or lupus profundus. Vasculitis was also revealed in the CLM lesions of 2 cases. The pathogenesis of CLM may be closely related to its two important features, the male pre ponderance and the association with SLE. Vasculopathy may also be involved in the development of CLM. (C) Munksgaard 1997.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SCANDINAVIAN UNIVERSITY PRESS  

The association between the type of precipitating autoantibodies and occurrence of avascular necrosis of bone (AVN) was examined. We prospectively analyzed clinical and laboratory findings of our 113 patients with SLE. Seven of 113 (6%) patients developed AVN. Anti-Re (SS-A) and anti-RNP antibodies coexisted in 3 of 7 AVN patients. The same combination of these two antibodies were observed in 1 without AVN. Antibodies to topoisomerase I were detected in 2 other patients with AVN but not in any of the patients without AVN. The coexistence of the former two or the presence of the latter one is rare in SLE. However, these (combination of) antibodies can be useful as a local ischemic marker predicting the development of AVN.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Mosby Inc.  

Background: Annular-polycyclic and papulosquamous lesions are associated with subacute cutaneous lupus erythematosus (SCLE). In some Asian cases, annular erythema has been associated with Sjogren's syndrome (SS). However, the relation between the two is unclear. Objective: Our purpose was to clarify the clinical manifestations and immunologic features of patients with annular erythema. Methods: This study included 15 patients with annular erythema. Systemic, serologic, and genetic findings were analyzed. Results: Histologic examination showed perivascular and periappendageal lymphocytic infiltrates in all patients. However, LE-specific epidermal changes were observed in only three (20%). Although all patients at least partially demonstrated features of LE or SS, eight (53%) fulfilled the American Rheumatism Association criteria for systemic LE (SLE) and five (33%) were diagnosed with SS. Renal (20%) and central nervous system (7%) involvement was observed. Anti-Ro(SS-A) and anti-La(SS-B) antibodies were detected in nine (60%) and seven (47%) patients, respectively. There were no histocompatibility antigen (HLA) haplotype differences. Conclusion: Annular erythema in Asian patients is the counterpart of subacute skin lesions of LE in whiles, except for the paucity of LE-specific histopathologic findings and HLA-DR3 tissue type.

DOI： 10.1016/S0190-9622(97)70283-4

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE LTD  

We studied the in vitro effect of testosterone on spontaneous immunoglobulin production by human peripheral blood mononuclear cells (PBMC). Testosterone inhibited IgG and IgM production by PBMC both from males and females. The inhibitory effect of testosterone was revealed at doses more than 1 nM, increased dose-dependently, and reached a plateau at 100 nM. At doses &lt;1000 nM, testosterone did not reduce cell viability. Testosterone treatment reduced IgG production by 59.0% and that of IgM by 61.3% compared with control. Immunoglobulin production by B cells was also suppressed by testosterone, though the magnitude of the suppressive effect on B cells was lower than that on whole PBMC; testosterone-induced decrease of IgG production compared with control was 26.9% and that of IgM was 24.9%. Exogenous IL-6 partially restored the impaired immunoglobulin production of testosterone-treated PBMC; IgG production in testosterone culture was increased by IL-6 from 35.6% to 66.5% of control and that of IgM was also increased from 38.9% to 71.2%, respectively. Testosterone treatment reduced IL-6 production of monocytes by 78.4% compared with control. but neither affected that of T cells or B cells. These results suggest that testosterone may suppress immunoglobulin production of human PBMC directly by inhibiting B cell activity and indirectly by reducing IL-6 production of monocytes. It is thus indicated that this hormone may have protective and therapeutic effects on human autoimmune diseases.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background: Cutaneous manifestations of systemic lupus erythematosus (SLE) in men have not been precisely investigated. Objective: The purpose of this study is to define the clinical features of SLE in men, focusing on skin lesions, Methods: The clinical and laboratory manifestations of 28 male and 111 female patients were compared. Results: Widespread discoid lupus erythematosus (DLE) and papular and nodular mucinosis (PNM) were significantly more common in men than in women, Serum sex hormone levels were within the normal range in all male patients examined, Conclusion: This study suggests that gender differences exist in SLE and that male patients tend to present with atypical cutaneous manifestations.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Recently, we defined the antigenic epitope recognized by the human monoclonal antibody L94 to be a protein with a C-terminal sequence of alanine-proline (AP). An antigenic peptide no. 707 (RVAALARDAP), which was identified by the use of cDNA libraries of an antigen positive melanoma cell line M14, was evaluated for cellular immune responses in melanoma patients. PBMC from 16 of 19 melanoma patients were shown to lyse autologous B lymphoblastoid cell lines (BCL) pulsed with synthetic peptide no. 707 (hereafter no. 707). This specific cytotoxicity to the peptide significantly increased in 84% of melanoma patients after in vivo immunization with a melanoma cell vaccine (MCV). In contrast, peptide specific cytotoxicity was observed in only one of 19 normal volunteer donors. In vitro restimulation of MCV treated patients' PBMC with no. 707 augmented cytotoxicity against autologous no. 707-pulsed BCL. This cytotoxicity was specific to the C-terminal sequence AP, since the removal of C-terminal AP completely abolished the specific lysis. no. 707 restimulation of PBMC enhanced cytotoxicity against autologous melanomas. Autologous melanoma and peptide-pulsed BCL targets were lysed by CDs + CTL in a HLA class I-restricted manner. The strong cytotoxicity was obtained from patients of HLA A24. CTL lysis of autologous no. 707-pulsed BCL was partially blocked by unlabeled autologous melanomas in a cold target inhibition test. This suggested that the epitope identical or cross-reactive to no. 707 may be presented on the melanoma cell surface by HLA class I antigens. Our findings suggest that peptide no. 707 presented on human melanoma cells is recognized by CTL and that C-terminal AP plays a critical role in both antibody and T cell recognition.

DOI： 10.1016/0161-5890(95)00020-F

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

The decapeptide 810 (QDLTMKYQIF) contains the antigenic epitope (KYQI) recognized by human mAb L92. This sequence is found in a 43-kDa protein associated with human melanoma M14. We examined the expression of 810 in human cells and its involvement in the cellular immune responses of melanoma patients. Nineteen stage III melanoma patients and 19 normal donors were studied for their responses to 810. All patients were immunized in vivo with an allogeneic melanoma cell vaccine. PBMC cytotoxicity was tested on autologous EBV-transformed B lymphoblastoid cell lines (BCL) pulsed with 810 and autologous melanomas. Proliferative responses of PBMC to 810 were evaluated by using [H-3]Tdr incorporation assays. Western blotting revealed that the 43-kDa protein was not specific to melanoma but was common to various cells. However, the percentage of cytotoxicity of PBMC against autologous 810-pulsed BCL was significantly greater in melanoma patients than in normal controls (p &lt; 0.005). Cytotoxicity was increased after melanoma cell vaccine immunization in 15 patients (78%). Proliferative responses to 810 were observed only in melanoma patients and were enhanced in 12 patients (63%) after vaccination. Restimulation of PBMC from vaccinated patients with 810 increased cytotoxicity against both autologous 810-pulsed BCL and melanomas. These targets were lysed by CD8(+) T lymphocytes in an HLA class I-restricted manner. HLA-A2 and -A11 seemed to serve as the 810-presenting molecule. Our findings indicate that 810 may function as an epitope for CTL on human melanoma and can be used as a vaccine.

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記述言語：日本語   出版者・発行元：金原出版(株)  

＜文献概要＞64歳,男性。非活動性B型肝炎ウイルスキャリア。初診時,扁平隆起する紅色小結節が頸部,腰背部,両前腕,両下腿に多発集簇していた。病理組織像は非乾酪性類上皮細胞肉芽腫であった。HBs抗原陽性,HBe抗体陽性。眼底検査で網脈絡膜萎縮を認めた。結節型皮膚サルコイド,眼サルコイドーシスと診断した。初診2ヵ月後,顔面にびまん浸潤型サルコイドと考えられる暗紅色斑が出現した。核酸アナログを併用してプレドニゾロン15mg内服を開始し,皮疹は軽快した。自験例ではB型肝炎ウイルスに対するTh1反応の活性化がサルコイドーシスの肉芽腫形成を誘導した可能性がある。B型肝炎ウイルスキャリアにステロイドを全身投与する場合,ウイルス再活性化防止対策が必要である。

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記述言語：日本語   出版者・発行元：日本皮膚科学会-西部支部  

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：日本皮膚科学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2015125219

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：NATURE PUBLISHING GROUP  

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記述言語：日本語   出版者・発行元：Japanese Dermatological Association  

16歳以上の円形脱毛症患者71例に対し，セファランチンと他剤の併用療法を行い，病型別にその臨床効果，併用薬剤数，有害事象等について検討した．セファランチンに併用された薬剤（治療法）は，グリチルリチン製剤，ステロイド外用剤，塩化カルプロニウム液，液体窒素療法であった．全71例における改善度は著効8例（11.3%），有効34例（47.9%），やや有効23例（32.4%），不変5例（7.0%），悪化1例（1.4%）で，有効以上の症例は42例であり，有効率は59.2%であった．単発型の治療は，2種類の薬剤を用いた症例が最も多く9例で，そのうちの7例（77.8%）がセファランチンとグリチルリチン製剤あるいは第2世代抗ヒスタミン剤（以下グリチルリチン製剤等）の経口剤の併用であった．多発型においては各々の併用薬剤と対照群との有効率を比較すると，各種併用薬，併用療法を用いた群と用いなかった群の有効率の間に有意差は認められなかった．次に二剤併用群の有効以上の症例の治療内容を検討してみた．その結果セファランチンと塩化カルプロニウム9例中8例（88.9%），セファランチンとステロイド外用剤が4例中3例（75.0%）であり，経口剤と外用剤の併用が行われた症例が経口剤のみを併用したセファランチン・グリチルリチン製剤群11例中5例（45.4%）に比し高い有効率があり有意差が認められた（p<0.05）．以上よりセファランチンは他剤特に塩化カルプロニウム液ないしはステロイド外用剤との併用療法が臨床的に有効であると言える．

DOI： 10.14924/dermatol.123.9

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記述言語：日本語  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：NATURE PUBLISHING GROUP  

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記述言語：日本語  

DOI： 10.11477/mf.1412103168

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記述言語：日本語   出版者・発行元：日本皮膚科学会  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2012117371

記述言語：日本語  

J-GLOBAL

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記述言語：英語   出版者・発行元：(一社)日本医真菌学会  

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記述言語：日本語   出版者・発行元：医学書院  

DOI： 10.11477/mf.1412102939

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記述言語：日本語   出版者・発行元：診断と治療社  

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その他リンク： http://search.jamas.or.jp/link/ui/2011148248

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その他リンク： http://search.jamas.or.jp/link/ui/2011018419

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：NATURE PUBLISHING GROUP  

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記述言語：日本語   出版者・発行元：南江堂  

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その他リンク： http://search.jamas.or.jp/link/ui/2010107276

記述言語：日本語   出版者・発行元：金原出版  

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その他リンク： http://search.jamas.or.jp/link/ui/2010025087

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その他リンク： http://search.jamas.or.jp/link/ui/2009305755

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その他リンク： http://search.jamas.or.jp/link/ui/2008210593

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記述言語：日本語   出版者・発行元：日本香粧品学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2008121278

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その他リンク： http://search.jamas.or.jp/link/ui/2007206600

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その他リンク： http://search.jamas.or.jp/link/ui/2005209762

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