title: Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells.
abstract: Liver fibrosis is a consequence of chronic liver disease, causing morbidity and mortality. Interleukin-33 (IL-33) is a critical mediator of inflammation, which may be involved in the development of liver fibrosis. Here, we investigated the role of IL-33 in human patients and experimental bile-duct ligation (BDL)-induced fibrosis in mice. We report increased hepatic IL-33 expression in the murine BDL model of fibrosis and in surgical samples obtained from patients with liver fibrosis. Liver injury, inflammatory cell infiltration and fibrosis were reduced in the absence of the IL-33/ST2 receptor, and the activation of hepatic stellate cells (HSCs) was decreased in ST2-deficient mice. Recombinant IL-33 activated HSCs isolated from C57BL/6 mice, leading to the expression of IL-6, TGF-β, α-SMA and collagen, which was abrogated in the absence of ST2 or by pharmacological inhibition of MAPK signaling. Finally, administration of recombinant IL-33 significantly increased hepatic inflammation in sham-operated BL6 mice but did not enhance BDL-induced hepatic inflammation and fibrosis. In conclusion, BDL-induced liver inflammation and fibrosis are dependent on ST2 signaling in HSCs, and therefore, the IL-33/ST2 pathway may be a potential therapeutic target in human patients with chronic hepatitis and liver fibrosis.
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Department of Liver Surgery, National Health and Family Planning Commission, The First Affiliated Hospital of Nanjing Medical University,, Nanjing, Jiangsu, P.R. China.|Molecular Immunology and Embryology, UMR 7355, CNRS, University of Orleans, Orléans, France.|IIDMM, University of Cape Town, Cape Town, South Africa.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Department of Liver Surgery, National Health and Family Planning Commission, The First Affiliated Hospital of Nanjing Medical University,, Nanjing, Jiangsu, P.R. China.|Molecular Immunology and Embryology, UMR 7355, CNRS, University of Orleans, Orléans, France.|IIDMM, University of Cape Town, Cape Town, South Africa.
authors.forename: Qianghui
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Department of Liver Surgery, National Health and Family Planning Commission, The First Affiliated Hospital of Nanjing Medical University,, Nanjing, Jiangsu, P.R. China.
authors.forename: Runqiu
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Department of Liver Surgery, National Health and Family Planning Commission, The First Affiliated Hospital of Nanjing Medical University,, Nanjing, Jiangsu, P.R. China.|Department of General Surgery, People's Hospital of Gaochun, Nanjing, Jiangsu, P.R. China.
authors.forename: Long
authors.initials: L
authors.lastname: Lv
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Department of Liver Surgery, National Health and Family Planning Commission, The First Affiliated Hospital of Nanjing Medical University,, Nanjing, Jiangsu, P.R. China.
authors.forename: Siamak S
authors.initials: SS
authors.lastname: Shoto
authors.affiliation: Molecular Immunology and Embryology, UMR 7355, CNRS, University of Orleans, Orléans, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maillet
authors.affiliation: Molecular Immunology and Embryology, UMR 7355, CNRS, University of Orleans, Orléans, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Quesniaux
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Department of Liver Surgery, National Health and Family Planning Commission, The First Affiliated Hospital of Nanjing Medical University,, Nanjing, Jiangsu, P.R. China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Tang
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Department of Liver Surgery, National Health and Family Planning Commission, The First Affiliated Hospital of Nanjing Medical University,, Nanjing, Jiangsu, P.R. China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Department of Liver Surgery, National Health and Family Planning Commission, The First Affiliated Hospital of Nanjing Medical University,, Nanjing, Jiangsu, P.R. China. sunbc@njmu.edu.cn.
authors.forename: Beicheng
authors.initials: B
authors.lastname: Sun
authors.affiliation: Molecular Immunology and Embryology, UMR 7355, CNRS, University of Orleans, Orléans, France. bryffel@cnrs-orleans.fr.|IIDMM, University of Cape Town, Cape Town, South Africa. bryffel@cnrs-orleans.fr.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D000328:Adult; D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D005260:Female; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000172:deficiency / Q000378:metabolism; D000067596:Interleukin-33 / Q000378:metabolism*; D008026:Ligation; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D011994:Recombinant Proteins
keywords: IL-33; ST2; hepatic stellate cells; liver fibrosis