IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO

被引：88

作者：

Fang, Sijie ^{[1
,2
]}

Huang, Yazhuo ^{[1
]}

Wang, Shuaiwei ^{[2
]}

Zhang, Yidan ^{[1
]}

Luo, Xuerui ^{[2
]}

Liu, Luyan ^{[2
]}

Zhong, Sisi ^{[1
]}

Liu, Xingtong ^{[1
]}

Li, Dan ^{[2
]}

Liang, Rui ^{[2
]}

Miranda, Piccioni ^{[2
]}

Gu, Ping ^{[1
]}

Zhou, Huifang ^{[1
]}

Fan, Xianqun ^{[1
]}

Li, Bin ^{[2
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 9, Dept Ophthalmol, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China

[2] Chinese Acad Sci, Univ Chinese Acad Sci,Med Sch, Inst Pasteur Shanghai,Shanghai Inst Biol Sci, Ctr Excellence Mol Cell Sci,Unit Mol Immunol,Key, 320 Yueyang Rd, Shanghai 200031, Peoples R China

来源：

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2016年 / 101卷 / 08期

基金：

中国国家自然科学基金;

关键词：

THYROID-ASSOCIATED OPHTHALMOPATHY; HUMAN COLONIC MYOFIBROBLASTS; NF-KAPPA-B; GRAVES OPHTHALMOPATHY; INFLAMMATORY RESPONSES; SYSTEMIC-SCLEROSIS; LIVER FIBROSIS; TH17; CELLS; ACTIVATION; DISEASE;

D O I：

10.1210/jc.2016-1882

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Context: The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO. Objective: We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO. Design/Setting/Participants: Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects. Main Outcome Measures: Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed. Results: Here, we showed a significantly higher proportion of IL-17A-producing T cells in TAO patients and the recruitment of both CD4(+) and CD8(+) T cells in TAO orbits. TAO orbital tissues expressed more IL-17A receptor, IL-17A, and its related cytokines, with severe fibrotic change compared with normal controls. Furthermore, we validated that IL-17A could enhance the proinflammatory function of OFs and stimulate the production of extracellular matrix proteins in OFs but not eyelid fibroblasts. The mechanisms involved in this enhancement mainly relied onMAPKactivation. Finally, weobserved that the deubiquitinase inhibitor vialinin A could down-regulate retinoic acid receptor-related orphan receptor-gamma t expression and decrease IL-17A level in TAO patients. Conclusion: Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of retinoic acid receptor-related orphan receptor-gamma t level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future.

引用

页码：2955 / 2965

页数：11

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