title: Ifit1 Protects Against Lipopolysaccharide and D-galactosamine-Induced Fatal Hepatitis by Inhibiting Activation of the JNK Pathway.
abstract: Treatment of mice with lipopolysaccharide (LPS) and the liver-specific transcriptional inhibitor D-(+)-galactosamine (GalN) induces fatal hepatitis, which is mediated by tumor necrosis factor α (TNF-α) and characterized by massive hepatic apoptosis. Previous studies suggest that GalN increases the sensitivity to LPS/TNF-α, probably by blocking the transcription of protective factors, but the identity of most of these factors is still unclear. Here, we report that Ifit1 protects against LPS/GalN-induced fatal hepatitis. Forced expression of Ifit1 in hepatocytes significantly diminished TNF-α-mediated apoptosis. Moreover, targeted expression of Ifit1 in the liver by recombinant adeno-associated virus serotype 8 protected mice from LPS/GalN-induced lethal hepatitis, which was associated with the inhibition of TNF-α-mediated activation of the c-Jun N-terminal kinase (JNK)-Bim cascade. Furthermore, Ifit1 bound to a scaffolding protein Axin and inhibited its function to mediate JNK activation. Together, our data demonstrate that Ifit1 is a novel protective factor that inhibits LPS/GalN-induced (TNF-α-mediated) fatal hepatitis, suggesting that Ifit1 is a potential therapeutic target for treatment of inflammatory liver diseases.
authors.affiliation: School of Medicine, Nankai University, Tianjin Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University.
authors.forename: Antao
authors.initials: A
authors.lastname: Chang
authors.affiliation: School of Medicine, Nankai University, Tianjin.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Medicine, Nankai University, Tianjin.
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Shen
authors.affiliation: School of Medicine, Nankai University, Tianjin.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Gao
authors.affiliation: School of Medicine, Nankai University, Tianjin.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: School of Medicine, Nankai University, Tianjin.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: School of Medicine, Nankai University, Tianjin.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology, School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chuang
authors.affiliation: Department of Cell and Molecular Biology, Scripps Research Institute, La Jolla, California.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
authors.affiliation: School of Medicine, Nankai University, Tianjin.
authors.forename: Chenghu
authors.initials: C
authors.lastname: Liu
authors.affiliation: School of Medicine, Nankai University, Tianjin.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005688:Galactosamine / Q000009:adverse effects; D006505:Hepatitis / Q000188:drug therapy*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C092573:Ifit1 protein, mouse; D008070:Lipopolysaccharides; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Ifit1; JNK; LPS; TNF-α; fatal hepatitis