title: Antagonism of Interleukin-17A ameliorates experimental hepatic fibrosis by restoring the IL-10/STAT3-suppressed autophagy in hepatocytes.
abstract: Interleukin-17A has been identified as a driver of hepatic stellate cell activation and plays a critical role in the pathogenesis of hepatic fibrosis. However, the underlining fibrosis-promoting mechanism of IL-17A is far from understood. Here we aimed to define whether hepatocytes directly respond to IL-17A stimulation and are associated with the development of hepatic fibrosis. The functional significance of IL-17A was evaluated in bile duct ligation (BDL) or thioacetamide (TAA) injection-induced mouse models of hepatic fibrosis. Human cirrhosis and control tissues were obtained from the patients with cirrhosis who received an open surgical repair process. Neutralizing IL-17A promoted the resolution of BDL or TAA-induced acute or chronic inflammation and fibrosis, resulted in a shift of the suppressive immune response in fibrotic liver toward a Th1-type immune response, and restored autophagy activity in both cholestatic and hepatotoxic liver injury induced fibrotic liver tissues, which was accompanied by a significant inhibition of STAT3 phosphorylation. Moreover, we found that IL-17A stimulated the concentration-and time-dependent phosphorylation of STAT3 in AML-12 liver cells. Blocking STAT3 with a specific inhibitor STATTIC or STAT3 siRNA protected from the IL-17A-induced autophagy suppression in AML-12 cells, indicating that STAT3 mediates IL-17A-suppressed autophagy. Administration of IL-10, which activated STAT3 and inhibited autophagy, reversed the therapeutic effect of IL-17A antagonism in vivo. Our study suggests that the IL-17A/STAT3 signaling pathway plays a crucial role in the pathogenesis of hepatic fibrosis through suppressing hepatocellular autophagy and that blocking this pathway may provide therapeutic benefits for the treatment of hepatic fibrosis.
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Zhang
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Su
authors.initials: S
authors.lastname: Mi
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Ji-Chao
authors.initials: JC
authors.lastname: Zhou
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Xiao-Xi
authors.initials: XX
authors.lastname: Lv
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Jiao-Jiao
authors.initials: JJ
authors.lastname: Yu
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Zhuo-Wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002779:Cholestasis / Q000150:complications; D003499:Cyclic S-Oxides / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013853:Thioacetamide; D014162:Transfection
chemical_list: D057134:Antibodies, Neutralizing; D003499:Cyclic S-Oxides; C556062:IL10 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C517409:stattic; D013853:Thioacetamide; D016753:Interleukin-10
keywords: cirrhosis; inflammation; liver injury; neutralizing antibody; p62