Research Article| Volume 72, ISSUE 5, P946-959, May 2020

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

Published:December 31, 2019DOI:


      • 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.

      Background & Aims

      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.

      Lay summary

      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.

      Graphical abstract


      Linked Article

      • Battling IL-17, the troublemaker in alcohol-induced hepatocellular carcinoma
        Journal of HepatologyVol. 72Issue 5
        • Preview
          Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide.1 The primary risk factors for HCC include chronic hepatitis B and C viral infections, non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver diseases (ALD). While recent clinical advances have considerably improved the management of HBV/HCV-driven liver diseases, both NAFLD and ALD are expected to increase the global burden of HCC significantly.1 Though NAFLD and ALD share similar histological features, ALD is the main cause of liver-related mortality worldwide.
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