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J Hepatol. 2019 Dec 31. pii: S0168-8278(19)30761-5. doi: 10.1016/j.jhep.2019.12.016. [Epub ahead of print]

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

Author information

1
Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Surgery, University of California San Diego, La Jolla, CA, USA.
2
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
3
Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
4
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
5
Department of Medicine, McGill University and the McGill University Health Center, Montreal, QC, Canada.
6
Department of Biology, University of North Carolina at Charlotte, Charlotte, NC, USA.
7
Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of USC, Los Angeles, CA, USA; Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
8
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
9
Department of Surgery, University of California San Diego, La Jolla, CA, USA. Electronic address: tkisseleva@ucsd.edu.

Abstract

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

ALD; Alcoholic liver disease; Cholesterol synthesis; Fibrosis; HCC; Hepatocellular carcinoma; IL-17 signaling; Inflammation; Mutational signatures

PMID:
31899206
DOI:
10.1016/j.jhep.2019.12.016

Conflict of interest statement

Conflict of interest The authors declare they have no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details.

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