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

Autor: Ludmil B. Alexandrov, Hsiao-Yen Ma, Takahiro Nishio, Jun Xu, Xiao Liu, Pnina Brodt, Mengxi Sun, Ju Youn Kim, Alan R. Saltiel, Gen Yamamoto, Daniel Karin, Oswald Quehenberger, Gabriel Karin, Christopher Benner, Tatiana Kisseleva, Sara Brin Rosenthal, Hidekazu Tsukamoto, Edward A. Dennis, Iain H. McKillop, David A. Brenner, Yukinori Koyama, Shuang Liang, Peng Zhao, Sven Heinz, Michael Karin, Bin Gao
Rok vydání: 2020
Předmět:
Liver Cirrhosis
Male
Chemokine
Hepatocellular carcinoma
Carcinogenesis
medicine.medical_treatment
Inbred C57BL
Oral and gastrointestinal
Alcohol Use and Health
Substance Misuse
Mice
Fibrosis
Receptors
2.1 Biological and endogenous factors
HCC
Aetiology
Cancer
Mice
Knockout
Receptors
Interleukin-17
biology
Liver Diseases
Liver Disease
Interleukin-17
Liver Neoplasms
Alcoholic
IL-17 signaling
CXCL1
Alcoholism
Cytokine
Cholesterol synthesis
Public Health and Health Services
Tumor necrosis factor alpha
Interleukin 17
medicine.symptom
Signal Transduction
Liver Cancer
Carcinoma
Hepatocellular
Kupffer Cells
Knockout
Chronic Liver Disease and Cirrhosis
Clinical Sciences
Mutational signatures
Inflammation
Rare Diseases
medicine
Animals
Humans
Liver Diseases
Alcoholic
Nutrition
Gastroenterology & Hepatology
Ethanol
Hepatology
Animal
business.industry
Inflammatory and immune system
Carcinoma
Hepatocellular
Alcoholic liver disease
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
Good Health and Well Being
ALD
Disease Models
Hepatocytes
biology.protein
Cancer research
Hepatic stellate cell
Digestive Diseases
Transcriptome
business
Gene Deletion
Zdroj: Journal of hepatology, vol 72, iss 5
ISSN: 0168-8278
DOI: 10.1016/j.jhep.2019.12.016
Popis: 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.
Databáze: OpenAIRE
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