肺纤维化
炎症
自噬
特发性肺纤维化
促炎细胞因子
纤维化
白细胞介素17
博莱霉素
免疫学
癌症研究
转化生长因子
免疫系统
肺
医学
生物
病理
内科学
细胞凋亡
化疗
生物化学
作者
Su Mi,Zhe Li,Hongzhen Yang,Hong Liu,Jia-Ping Wang,Yonggang Ma,Xiaoxing Wang,Hanzhi Liu,Wei Sun,Zhuowei Hu
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2011-08-13
卷期号:187 (6): 3003-3014
被引量:329
标识
DOI:10.4049/jimmunol.1004081
摘要
Abstract Pulmonary fibrosis is the pathologic basis for a variety of incurable human chronic lung diseases. IL-17A, a glycoprotein secreted from IL-17–producing cells, has recently been shown to be a proinflammatory cytokine involved in chronic inflammation and autoimmune disease. In this study, we report that IL-17A increased the synthesis and secretion of collagen and promoted the epithelial–mesenchymal transition in alveolar epithelial cells in a TGF-β1–dependent manner. Using in vivo fibrotic models, we found IL-17A expression to be elevated and IL-17A–associated signaling pathways to be activated in fibrotic lung tissues. Neutralization of IL-17A in vivo promoted the resolution of bleomycin-induced acute inflammation, attenuated pulmonary fibrosis, and increased survival. Additionally, IL-17A antagonism inhibited silica-induced chronic inflammation and pulmonary fibrosis. Targeting IL-17A resulted in a shift of the suppressive immune response in fibrotic lung tissue toward a Th1-type immune response, and it effectively induced autophagy, which promoted the autophagic degradation of collagen and autophagy-associated cell death. Moreover, IL-17A was found to attenuate the starvation-induced autophagy, and autophagy modulators regulated collagen degradation in the alveolar epithelial cells in a TGF-β1–independent manner. Administration of 3-methylamphetamine, an autophagy inhibitor, reversed the therapeutic efficacy of IL-17A antagonism in pulmonary fibrosis. Our studies indicate that IL-17A participates in the development and progression of pulmonary fibrosis in both TGF-β1–dependent and –independent manners and that the components of the IL-17A signaling pathway are potential therapeutic targets for the treatment of fibroproliferative lung diseases.
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