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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Actins / biosynthesis
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Actins / genetics
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Adult
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Animals
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Carbon Tetrachloride Poisoning / complications
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Carcinoma, Hepatocellular / chemistry
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Carcinoma, Hepatocellular / etiology
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Carcinoma, Hepatocellular / surgery
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Chemical and Drug Induced Liver Injury / etiology
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Chemical and Drug Induced Liver Injury / metabolism
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Chemical and Drug Induced Liver Injury / pathology
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Collagen / biosynthesis
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Collagen / genetics
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Cytokines / biosynthesis
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Cytokines / genetics
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Female
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology
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Hemangioma / chemistry
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Hemangioma / surgery
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Hepatectomy
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Hepatic Stellate Cells / metabolism*
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Hepatic Stellate Cells / pathology
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Hepatitis B, Chronic / complications
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Hepatitis, Animal / chemically induced
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Hepatitis, Animal / metabolism
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Hepatitis, Animal / pathology
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Humans
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Interleukin-17 / analysis
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Interleukin-17 / biosynthesis
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Interleukin-17 / genetics
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Interleukin-17 / pharmacology
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Interleukin-17 / physiology*
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Liver Cirrhosis / complications
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Liver Cirrhosis / etiology*
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Liver Cirrhosis / metabolism
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Liver Cirrhosis / pathology
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Liver Neoplasms / chemistry
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Liver Neoplasms / surgery
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Male
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Mice
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Mice, Knockout
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Middle Aged
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Neutrophils / physiology
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Nuclear Receptor Subfamily 1, Group F, Member 3 / analysis
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Protein Kinase Inhibitors / pharmacology
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Receptors, Interleukin-17 / deficiency
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Recombinant Proteins / pharmacology
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Th17 Cells / immunology
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Th17 Cells / metabolism
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / genetics
Substances
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Actins
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Cytokines
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IL17A protein, human
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Il17ra protein, mouse
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Interleukin-17
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Protein Kinase Inhibitors
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Receptors, Interleukin-17
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Recombinant Proteins
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Transforming Growth Factor beta
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Collagen