IL-17 signaling in inflammatory cells , Kupffer cells and Hepatic Stellate cells exacerbates liver fibrosis

Background—IL-17 signaling has been implicated in lung and skin fibrosis. Here we examined the role of IL-17 signaling in the pathogenesis of liver fibrosis. Methods—Using cholestatic and hepatotoxic models of liver injury, the development of liver fibrosis in wild type mice was compared to IL-17RA−/− mice, and to bone marrow chimeric mice devoid of IL-17 signaling in immune cells and Kupffer cells (IL-17RA−/−→wt and IL-17A−/− →wt mice), or in liver resident cells (Wt→ IL-17RA−/− mice). Results—We determined that IL-17A and its receptor is highly induced in liver injury and has a strong pro-fibrogenic effect on both inflammatory and liver resident cells. IL-17 signaling facilitates production of IL-6, IL-1β, and TNF-α by inflammatory cells, and increases the expression of TGF-β1, the major pro-fibrogenic cytokine. IL-17 directly induces collagen Type I production in hepatic stellate cells (HSCs) via activation of the Stat3 signaling pathway. Mice devoid of Stat3 signaling in HSCs (GFAPStat3−/− mice) are less susceptible to fibrosis. Furthermore, deletion of IL-23 in immune cells results in attenuation of liver fibrosis, while deletion of IL-22 exacerbates fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protects mice from BDL-induced liver fibrosis. Conclusions—IL-17 induces liver fibrosis through multiple mechanisms and may serve as an attractive target for anti-fibrotic therapy. *Correspondence: tkisseleva@ucsd.edu, 9500 Gilman Drive # 0702, La Jolla, California, 92093, Tel: 1-858-822-5339. Conflict of interests: none to declare Author contribution: FM designed the study, acquired the data, wrote the manuscript; Y-H.P, T.A, S.I.G., M.C., K.I., C.H.O. acquired the data; K.W., S.I.G. and K.L provided support and critical revision of the manuscript, D.A.B. designed the study and provided critical revision of the manuscript, TK designed the study, wrote the manuscript. NIH Public Access Author Manuscript Gastroenterology. Author manuscript; available in PMC 2013 April 25. Published in final edited form as: Gastroenterology. 2012 September ; 143(3): 765–76.e1-3. doi:10.1053/j.gastro.2012.05.049. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript