Details

Autor(en) / Beteiligte

• Ma, Hsiao-Yen
• Yamamoto, Gen
• Xu, Jun
• Liu, Xiao
• Karin, Daniel
• Kim, Ju Youn
• Alexandrov, Ludmil B.
• Koyama, Yukinori
• Nishio, Takahiro
• Benner, Chris
• Heinz, Sven
• Rosenthal, Sara B.
• Liang, Shuang
• Sun, Mengxi
• Karin, Gabriel
• Zhao, Peng
• Brodt, Pnina
• Mckillop, Iain H.
• Quehenberger, Oswald
• Dennis, Ed
• Saltiel, Alan
• Tsukamoto, Hidekazu
• Gao, Bin
• Karin, Michael
• Brenner, David A.
• Kisseleva, Tatiana

Titel

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

Ist Teil von

• Journal of hepatology, 2020-05, Vol.72 (5), p.946-959

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2020

Quelle

ScienceDirect

Beschreibungen/Notizen

• 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. [Display omitted] •IL-17 promotes alcohol-induced hepatocellular carcinoma.•IL-17 regulates activation of macrophages.•IL-17 facilitates tumor necrosis factor/tumor necrosis factor receptor-mediated lipogenesis in alcohol-damaged hepatocytes.•IL-17 promotes lipogenesis via activation of caspase-2-SP1-SREBP1/2-DHCR7 pathway.•IL-17 signaling prevents TNFR1 exocytosis in steatotic hepatocytes.