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IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation

Tan, Zhongming ; Qian, Xiaofeng ; Jiang, Runqiu ; Liu, Qianghui ; Wang, Youjing ; Chen, Chen ; Wang, Xuehao ; Ryffel, Bernhard ; Sun, Beicheng

The Journal of immunology (1950), 2013-08, Vol.191 (4), p.1835-1844 [Periódico revisado por pares]

United States

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Título:
IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation
Autor: Tan, Zhongming ; Qian, Xiaofeng ; Jiang, Runqiu ; Liu, Qianghui ; Wang, Youjing ; Chen, Chen ; Wang, Xuehao ; Ryffel, Bernhard ; Sun, Beicheng
Assuntos: Actins - biosynthesis ; Actins - genetics ; Adult ; Animals ; Carbon Tetrachloride Poisoning - complications ; Carcinoma, Hepatocellular - chemistry ; Carcinoma, Hepatocellular - etiology ; Carcinoma, Hepatocellular - surgery ; Chemical and Drug Induced Liver Injury - etiology ; Chemical and Drug Induced Liver Injury - metabolism ; Chemical and Drug Induced Liver Injury - pathology ; Collagen - biosynthesis ; Collagen - genetics ; Cytokines - biosynthesis ; Cytokines - genetics ; Female ; Gene Expression Regulation - drug effects ; Gene Expression Regulation - immunology ; Hemangioma - chemistry ; Hemangioma - surgery ; Hepatectomy ; Hepatic Stellate Cells - metabolism ; Hepatic Stellate Cells - pathology ; Hepatitis B, Chronic - complications ; Hepatitis, Animal - chemically induced ; Hepatitis, Animal - metabolism ; Hepatitis, Animal - pathology ; Humans ; Interleukin-17 - analysis ; Interleukin-17 - biosynthesis ; Interleukin-17 - genetics ; Interleukin-17 - pharmacology ; Interleukin-17 - physiology ; Liver Cirrhosis - complications ; Liver Cirrhosis - etiology ; Liver Cirrhosis - metabolism ; Liver Cirrhosis - pathology ; Liver Neoplasms - chemistry ; Liver Neoplasms - surgery ; Male ; MAP Kinase Signaling System - drug effects ; MAP Kinase Signaling System - physiology ; Mice ; Mice, Knockout ; Middle Aged ; Neutrophils - physiology ; Nuclear Receptor Subfamily 1, Group F, Member 3 - analysis ; Protein Kinase Inhibitors - pharmacology ; Receptors, Interleukin-17 - deficiency ; Recombinant Proteins - pharmacology ; Th17 Cells - immunology ; Th17 Cells - metabolism ; Transforming Growth Factor beta - biosynthesis ; Transforming Growth Factor beta - genetics
É parte de: The Journal of immunology (1950), 2013-08, Vol.191 (4), p.1835-1844
Notas: ObjectType-Article-1
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Descrição: 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.
Editor: United States
Idioma: Inglês

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IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation

Tan, Zhongming ; Qian, Xiaofeng ; Jiang, Runqiu ; Liu, Qianghui ; Wang, Youjing ; Chen, Chen ; Wang, Xuehao ; Ryffel, Bernhard ; Sun, Beicheng

United States

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