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-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 ... -  《-》

IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation.

Tan Z ，Qian X ，Jiang R ，Liu Q ，Wang Y ，Chen C ，Wang X ，Ryffel B ，Sun B ... -  《-》

Interleukin-17A plays a pivotal role after partial hepatectomy in mice.

Liver regeneration after partial hepatectomy (PH) is regulated by tumor necrosis factor (TNF)-α derived from the Kupffer cell. Furthermore, it was reported from our laboratory that interleukin (IL)-17A enhances the production of TNF-α by the Kupffer cell, suggesting that IL-17A may play a role in liver regeneration. The purpose was to determine the role of IL-17A and the spleen in liver regeneration after PH. Two mouse models including the wild-type (WT) mice or the IL-17A knockout (KO) mice underwent PH. Animals were killed at the designated time points; liver tissues were harvested for further investigation. Proliferation of hepatocytes was evaluated. Furthermore, the messenger RNA and protein expression of TNF-α and IL-6 were measured in the liver. In another set of experiments, the two animal models underwent splenectomy before PH. In an in vitro study, CD4-positive lymphocytes in the spleen were isolated from mice, and the number of IL-17A-positive cells was investigated. Liver regeneration was significantly impaired in the KO mice compared with the WT mice. This was associated with suppression of cell proliferation assessed by cell proliferation markers in the KO mice. In the WT mice that underwent splenectomy, liver regeneration was significantly delayed compared with animals without splenectomy. In contrast, splenectomy did not affect liver regeneration in the KO mice. IL-17A-positive lymphocytes increased significantly in the spleen in the WT mice after PH. These results indicate that IL-17A derived from CD4-positive lymphocytes in the spleen is a key regulator in liver regeneration after PH.

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

Pathological roles of bone marrow-derived stellate cells in a mouse model of alcohol-induced fatty liver.

Fujimiya T ，Liu J ，Kojima H ，Shirafuji S ，Kimura H ，Fujimiya M ... -  《-》