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IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease.
J Hepatol 2019JH

Abstract

BACKGROUND&AIMS

Chronic alcohol (EtOH) consumption is a leading risk factor for development of hepatocellular carcinoma (HCC), which is associated with marked increase of hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA.

METHODS

Genetic deletion and pharmacological blocking was used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC.

RESULTS

We demonstrate that global deletion of IL-17RA gene suppressed HCC in alcohol-fed DEN-challenged IL-17RA-/- and Mup-uPA/IL-17RA-/- mice compared to wild type mice. When the cell-specific role of IL-17RA signaling was examined, 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-17RAΔHSCs mice (deficient of IL-17RA in hepatic stellate cells (HSCs)). 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 to IL-17RAΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated expression of Cxcl1 and other chemokines, exhibited a striking defect in TNF-TNFR1-dependent Caspase-2-SREBP-1/2-DHCR7-mediated cholesterol synthesis, and upregulated production of anti-oxidant Vitamin D3. Pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 Ab suppressed progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for treatment of alcohol-induced HCC.

CONCLUSIONS

Overall, IL-17A is as a tumor promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC.

Authors+Show Affiliations

Department of Medicine; Department of Surgery.Department of Medicine; Department of Surgery.Department of Medicine; Department of Surgery.Department of Medicine; Department of Surgery.Department of Medicine.Department of Pharmacology.Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093, USA.Department of Medicine.Department of Medicine.Department of Medicine.Department of Medicine.Department of Medicine.Department of Medicine.Department of Medicine.Department of Medicine.Department of Pharmacology.Department of Medicine, McGill University and the McGill University Health Center, Montreal, QC H4A3J1, Canada.Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.Department of Medicine.Department of Medicine.Department of Pharmacology.Southern California Research Center for ALPD & Cirrhosis Department of Pathology Keck School of Medicine of USC, Los Angeles, CA 90033, USA; University of Southern California, and Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health, Bethesda, MD 20892, USA.Department of Pharmacology.Department of Medicine.Department of Surgery. Electronic address: tkisseleva@ucsd.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31899206

Citation

Ma, Hsiao-Yen, et al. "IL-17 Signaling in Steatotic Hepatocytes and Macrophages Promotes Hepatocellular Carcinoma in Alcohol-related Liver Disease." Journal of Hepatology, 2019.
Ma HY, Yamamoto G, Xu J, et al. IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J Hepatol. 2019.
Ma, H. Y., Yamamoto, G., Xu, J., Liu, X., Karin, D., Kim, J. Y., ... Kisseleva, T. (2019). IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. Journal of Hepatology, doi:10.1016/j.jhep.2019.12.016.
Ma HY, et al. IL-17 Signaling in Steatotic Hepatocytes and Macrophages Promotes Hepatocellular Carcinoma in Alcohol-related Liver Disease. J Hepatol. 2019 Dec 31; PubMed PMID: 31899206.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. AU - Ma,Hsiao-Yen, AU - Yamamoto,Gen, AU - Xu,Jun, AU - Liu,Xiao, AU - Karin,Daniel, AU - Kim,Ju Youn, AU - Alexandrov,Ludmil B, AU - Koyama,Yukinori, AU - Nishio,Takahiro, AU - Benner,Chris, AU - Heinz,Sven, AU - Rosenthal,Sara B, AU - Liang,Shuang, AU - Sun,Mengxi, AU - Karin,Gabriel, AU - Zhao,Peng, AU - Brodt,Pnina, AU - Mckillop,Iain H, AU - Quehenberger,Oswald, AU - Dennis,Ed, AU - Saltiel,Alan, AU - Tsukamoto,Hidekazu, AU - Gao,Bin, AU - Karin,Michael, AU - Brenner,David A, AU - Kisseleva,Tatiana, Y1 - 2019/12/31/ PY - 2019/06/11/received PY - 2019/12/04/revised PY - 2019/12/09/accepted PY - 2020/1/4/entrez KW - Alcoholic liver disease (ALD) KW - IL-17 signaling KW - cholesterol synthesis KW - fibrosis KW - hepatocellular carcinoma (HCC) KW - inflammation KW - mutational signatures JF - Journal of hepatology JO - J. Hepatol. N2 - BACKGROUND&AIMS: Chronic alcohol (EtOH) consumption is a leading risk factor for development of hepatocellular carcinoma (HCC), which is associated with marked increase of hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. METHODS: Genetic deletion and pharmacological blocking was used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC. RESULTS: We demonstrate that global deletion of IL-17RA gene suppressed HCC in alcohol-fed DEN-challenged IL-17RA-/- and Mup-uPA/IL-17RA-/- mice compared to wild type mice. When the cell-specific role of IL-17RA signaling was examined, 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-17RAΔHSCs mice (deficient of IL-17RA in hepatic stellate cells (HSCs)). 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 to IL-17RAΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated expression of Cxcl1 and other chemokines, exhibited a striking defect in TNF-TNFR1-dependent Caspase-2-SREBP-1/2-DHCR7-mediated cholesterol synthesis, and upregulated production of anti-oxidant Vitamin D3. Pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 Ab suppressed progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for treatment of alcohol-induced HCC. CONCLUSIONS: Overall, IL-17A is as a tumor promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/31899206/IL-17_signaling_in_steatotic_hepatocytes_and_macrophages_promotes_hepatocellular_carcinoma_in_alcohol-related_liver_disease L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(19)30761-5 DB - PRIME DP - Unbound Medicine ER -