Highlights
- •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.
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.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.Ann Intern Med. 2013; 158: 329-337
- Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology. 2011; 141: 1572-1585
- Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.J Hepatol. 2018; 69: 396-405
- Is hepatocellular cancer the same disease in alcoholic and nonalcoholic fatty liver diseases?.Gastroenterology. 2016; 150: 1710-1717
- Understanding the origins of human cancer.Science. 2015; 350: 1175
- Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.Nat Genet. 2015; 47: 505-511
- Hepatocellular carcinoma pathogenesis: from genes to environment.Nat Rev Cancer. 2006; 6: 674-687
- Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth.Nature. 2012; 491: 254-258
- Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis.Immunity. 2014; 41: 1052-1063
- Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent.J Exp Med. 2010; 207: 535-552
- Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.Gastroenterology. 2012; 143: 765-776.e3
- Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma.Cancer Cell. 2016; 30: 161-175
- Role of IL-17 and Th17 cells in liver diseases.Clin Dev Immunol. 2011; 2011: 345803
- Interleukin-17 family members and inflammation.Immunity. 2004; 21: 467-476
- Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been.Genes Dev. 2009; 23: 2578-2591
- ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P.Cell. 2018; 175: 133-145.e15
- Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity.Nature. 2017; 551: 340-345
- Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense.J Exp Med. 2001; 194: 519-527
- Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes.Am J Pathol. 2000; 157: 1963-1974
- Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology.Nat Commun. 2013; 4: 2823
- Chronic ethanol feeding accelerates hepatocellular carcinoma progression in a sex-dependent manner in a mouse model of hepatocarcinogenesis.Alcohol Clin Exp Res. 2012; 36: 641-653
- Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice.Hepatology. 2015; 61: 129-140
- Lipidomics reveals a remarkable diversity of lipids in human plasma.J Lipid Res. 2010; 51: 3299-3305
- A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis.N Engl J Med. 2011; 365: 1586-1596
- Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review.Pharmacogenomics J. 2016; 16: 411-429
- Cellular cholesterol trafficking and compartmentalization.Nat Rev Mol Cell Biol. 2008; 9: 125-138
- A role for cGMP in inducible nitric-oxide synthase (iNOS)-induced tumor necrosis factor (TNF) α-converting enzyme (TACE/ADAM17) activation, translocation, and TNF receptor 1 (TNFR1) shedding in hepatocytes.J Biol Chem. 2012; 287: 35887-35898
- Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors.Proc Natl Acad Sci U S A. 2004; 101: 1297-1302
- Rapid redistribution of Golgi proteins into the ER in cells treated with brefeldin A: evidence for membrane cycling from Golgi to ER.Cell. 1989; 56: 801-813
- Identification of ARTS-1 as a novel TNFR1 binding protein that promotes TNFR1 ectodomain shedding.J Clin Invest. 2002; 110: 515-526
- Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling.Nat Med. 2017; 23: 829-838
- Cholesterol biosynthesis from lanosterol. A concerted role for Sp1 and NF-Y-binding sites for sterol-mediated regulation of rat 7-dehydrocholesterol reductase gene expression.J Biol Chem. 2001; 276: 18153-18160
- Molecular cloning and expression of the human delta7-sterol reductase.Proc Natl Acad Sci U S A. 1998; 95: 1899-1902
- 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome.J Clin Invest. 2001; 108: 905-915
- The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact physically and functionally.J Lipid Res. 2015; 56: 888-897
- Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease.J Hepatol. 2013; 59: 344-350
- Lipid metabolite profiling identifies desmosterol metabolism as a new antiviral target for hepatitis C virus.J Am Chem Soc. 2012; 134: 6896-6899
- NADPH oxidase 1 in liver macrophages promotes inflammation and tumor development in mice.Gastroenterology. 2019; 156: 1156-1172.e6
Article info
Publication history
Published online: December 31, 2019
Accepted:
December 9,
2019
Received in revised form:
December 4,
2019
Received:
June 11,
2019
Identification
Copyright
© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
