title: IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation.
abstract: Liver fibrosis is a severe, life-threatening clinical condition resulting from nonresolving hepatitis of different origins. IL-17A is critical in inflammation, but its relation to liver fibrosis remains elusive. We find increased IL-17A expression in fibrotic livers from HBV-infected patients undergoing partial hepatectomy because of cirrhosis-related early-stage hepatocellular carcinoma in comparison with control nonfibrotic livers from uninfected patients with hepatic hemangioma. In fibrotic livers, IL-17A immunoreactivity localizes to the inflammatory infiltrate. In experimental carbon tetrachloride-induced liver fibrosis of IL-17RA-deficient mice, we observe reduced neutrophil influx, proinflammatory cytokines, hepatocellular necrosis, inflammation, and fibrosis as compared with control C57BL/6 mice. IL-17A is produced by neutrophils and T lymphocytes expressing the Th17 lineage-specific transcription factor Retinoic acid receptor-related orphan receptor γt. Furthermore, hepatic stellate cells (HSCs) isolated from naive C57BL/6 mice respond to IL-17A with increased IL-6, α-smooth muscle actin, collagen, and TGF-β mRNA expression, suggesting an IL-17A-driven fibrotic process. Pharmacologic ERK1/2 or p38 inhibition significantly attenuated IL-17A-induced HSC activation and collagen expression. In conclusion, IL-17A(+) Retinoic acid receptor-related orphan receptor γt(+) neutrophils and T cells are recruited into the injured liver driving a chronic, fibrotic hepatitis. IL-17A-dependent HSC activation may be critical for liver fibrosis. Thus, blockade of IL-17A could potentially benefit patients with chronic hepatitis and liver fibrosis.
authors.affiliation: Liver Transplantation Center of First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province 210029, People's Republic of China.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Tan
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Qian
authors.forename: Runqiu
authors.initials: R
authors.lastname: Jiang
authors.forename: Qianghui
authors.initials: Q
authors.lastname: Liu
authors.forename: Youjing
authors.initials: Y
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Beicheng
authors.initials: B
authors.lastname: Sun
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000150:complications; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000209:etiology / Q000601:surgery; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006391:Hemangioma / Q000737:chemistry / Q000601:surgery; D006498:Hepatectomy; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D019694:Hepatitis B, Chronic / Q000150:complications; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008103:Liver Cirrhosis / Q000150:complications / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000737:chemistry / Q000601:surgery; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009504:Neutrophils / Q000502:physiology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000032:analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053722:Receptors, Interleukin-17 / Q000172:deficiency; D011994:Recombinant Proteins / Q000494:pharmacology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000199:Actins; D016207:Cytokines; C508717:IL17A protein, human; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D047428:Protein Kinase Inhibitors; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen