Protective role of 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous ligand for arylhydrocarbon receptor, in chronic mite-induced dermatitis
Protective role of 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous ligand for arylhydrocarbon receptor, in chronic mite-induced dermatitis
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DOI：
10.1016/j.jdermsci.2018.02.014
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发表时间：
2018-06-01
影响因子：
4.6
通讯作者：
Furue, Masutaka
中科院分区：
文献类型：
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作者：
Kiyomatsu-Oda, Mari;Uchi, Hiroshi;Furue, Masutaka
背景：慢性湿疹如特应性皮炎会给患者带来显著的社会、经济和心理负担。除了常规的局部治疗外，对于大面积病变的患者，建议使用光疗。虽然免疫抑制被认为可以解释其主要效果，但光疗的潜在机制仍未解决。紫外线照射产生多种色氨酸光产物，包括6-甲酰基林多洛[3,2-b]-咔唑（FICZ）。FICZ是一种强效的内源性芳烃受体（AHR）激动剂；然而，FICZ在慢性湿疹中的生物学作用尚不清楚。目的：探讨FICZ对慢性湿疹（如特应性皮炎）的治疗作用。方法：用或不加FICZ刺激HaCaT细胞和正常人表皮角质形成细胞（NHEKs），然后进行定量逆转录酶聚合酶链反应、免疫荧光和siRNA处理。我们使用异位性皮炎样NC/Nga小鼠模型，用凡士林(R)作为对照，FICZ软膏或17-戊酸倍他米松软膏治疗小鼠2周。评估皮炎评分、经皮失水、组织学、皮肤屏障基因和蛋白的表达。结果：FICZ显著上调HaCaT细胞和NHEKs中聚丝蛋白的基因表达，并以ahr依赖的方式上调，但不影响其他屏障相关蛋白的基因表达。此外，与对照组小鼠相比，FICZ改善了NC/Nga小鼠的特应性皮炎样皮肤炎症、临床评分和经皮失水。在组织学上，FICZ显著降低了表皮和真皮的厚度以及肥大细胞的数量。局部FICZ也显著降低了il - 22的基因表达。结论：这些发现突出了FICZ-AHR的有益作用，为开发治疗慢性湿疹的新药提供了新的战略依据。(C) 2018年日本皮肤病研究学会。Elsevier B.V.版权所有。
Background: Chronic eczema such as atopic dermatitis imposes significant socio-econo-psychologic burdens on the affected individuals. In addition to conventional topical treatments, phototherapy is recommended for patients with extensive lesions. Although immunosuppression is believed to explain its primary effectiveness, the underlying mechanisms of phototherapy remain unsolved. Ultraviolet irradiation generates various tryptophan photoproducts including 6-formylindolo[3,2-b]-carbazole (FICZ). FICZ is known to be a potent endogenous agonist for aryl hydrocarbon receptor (AHR); however, the biological role of FICZ in chronic eczema is unknown.Objective: To investigate the effect of FICZ on chronic eczema such as atopic dermatitis.Methods: We stimulated HaCaT cells and normal human epidermal keratinocytes (NHEKs) with or without FICZ and then performed quantitative reverse transcriptase polymerase chain reaction, immunofluorescence, and siRNA treatment. We used the atopic dermatitis-like NC/Nga murine model and treated the mice for 2 weeks with either Vaseline (R) as a control, FICZ ointment, or betamethasone 17-valerate ointment. The dermatitis score, transepidermal water loss, histology, and expression of skin barrier genes and proteins were evaluated.Results: FICZ significantly upregulated the gene expression of filaggrin in both HaCaT cells and NHEKs in an AHR-dependent manner, but did not affect the gene expression of other barrier-related proteins. In addition, FICZ improved the atopic dermatitis-like skin inflammation, clinical scores, and transepidermal water loss in NC/Nga mice compared with those of control mice. On histology, FICZ significantly reduced the epidermal and dermal thickness as well as the number of mast cells. Topical FICZ also significantly reduced the gene expression of Il22.Conclusion: These findings highlight the beneficial role of FICZ-AHR and provide a new strategic basis for developing new drugs for chronic eczema. (C) 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.