标题:Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice
作者:Meng,F.;Wang,K.;Aoyama,T.;Grivennikov,S.I.;Paik,Y.;Scholten,D.;Cong,M.;Iwaisako,K.;Liu,X.;Zhang,M.;Sterreicher,C.H.;Stickel,F.;L
作者机构:Department of Medicine, University of California, San Diego, School of Medicine, San Diego, CA;Department of Hepatology, Qilu Ho
来源:Gastroenterology
出版年:2012
期:3
页码:765-776
关键词:Bone Marrow-Derived Macrophages;Immune Response;Mouse Model;Myofibroblast
摘要:BACKGROUND & AIMS: Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice. METHODS: Using cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA -/- mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells (IL-17RA -/- to wild-type and IL-17A -/- to wild-type mice) or liver resident cells (wild-type to IL-17RA -/- mice). RESULTS: In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-α by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducer and activator of transcription 3 (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells (GFAPStat3 -/- mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis. CONCLUSIONS: IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.
资源类型:期刊论文
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