Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.

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. 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). 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. IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.

Meng F ，Wang K ，Aoyama T ，Grivennikov SI ，Paik Y ，Scholten D ，Cong M ，Iwaisako K ，Liu X ，Zhang M ，Österreicher CH ，Stickel F ，Ley K ，Brenner DA ，Kisseleva T ... -  《-》

Interleukin-17A plays a pivotal role in cholestatic liver fibrosis in mice.

It was recently reported that serum interleukin (IL)-17 levels increased in liver fibrosis associated with human alcoholic liver disease. However, the role of IL-17 in liver fibrosis has not yet been elucidated. Therefore, the aim of this study was to evaluate the role of IL-17 on cholestatic liver fibrosis. IL-17A knockout (KO) and wild-type (WT) mice were subjected to bile duct ligation. Animals were sacrificed at designated times, and serum and liver tissues were collected. The mRNA expression of hepatic fibrotic markers was assessed, and distribution of activated hepatic stellate cells (HSCs) was determined by immunohistochemical staining. In an in vitro study, Kupffer cells (KCs) and HSCs were isolated from WT mice. KCs were cultured with IL-17A or IL-17F, and production of tumor necrosis factor α (TNF-α) and transforming growth factor β1 (TGF-β1) was measured. HSCs were cultured with IL-17A or IL-17F, and morphologic changes were assessed by immunohistochemical staining. Liver damage observed in the WT mice was significantly improved in the KO mice. Serum TNF-α and TGF-β1 levels were significantly decreased in the KO compared with the WT mice. The hepatic mRNA expression of TNF-α, TGF-β1, and collagen 1α1, which increased in the WT mice, also significantly decreased in the KO mice. Increased hepatic fibrosis in the WT mice was significantly improved in the KO mice. Cytokine production was increased in IL-17A-treated KCs. The most remarkable myofibroblast-like changes were observed in isolated HSCs in the presence of IL-17A. IL-17A was involved in the pathogenesis of cholestatic liver fibrosis by activation of both the KCs and HSCs.

Hara M ，Kono H ，Furuya S ，Hirayama K ，Tsuchiya M ，Fujii H ... -  《-》

Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines.

Lu DH ，Guo XY ，Qin SY ，Luo W ，Huang XL ，Chen M ，Wang JX ，Ma SJ ，Yang XW ，Jiang HX ... -  《-》

IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease.

Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens. We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra-/- and major urinary protein-urokinase-type plasminogen activator/Il-17ra-/- mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17raΔMΦ and Il-17raΔHep mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17raΔHSC mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17raΔMΦ mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17raΔHep mice developed the fewest tumors (compared with Il-17raΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D3. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC. Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC. IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.

Ma HY ，Yamamoto G ，Xu J ，Liu X ，Karin D ，Kim JY ，Alexandrov LB ，Koyama Y ，Nishio T ，Benner C ，Heinz S ，Rosenthal SB ，Liang S ，Sun M ，Karin G ，Zhao P ，Brodt P ，Mckillop IH ，Quehenberger O ，Dennis E ，Saltiel A ，Tsukamoto H ，Gao B ，Karin M ，Brenner DA ，Kisseleva T ... -  《-》

Antagonism of Interleukin-17A ameliorates experimental hepatic fibrosis by restoring the IL-10/STAT3-suppressed autophagy in hepatocytes.

Zhang XW ，Mi S ，Li Z ，Zhou JC ，Xie J ，Hua F ，Li K ，Cui B ，Lv XX ，Yu JJ ，Hu ZW ... -  《Oncotarget》