1. Ifit1 Protects Against Lipopolysaccharide and D-galactosamine-Induced Fatal Hepatitis by Inhibiting Activation of the JNK Pathway.
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Antao Chang, Yanan Chen, Wenzhi Shen, Ruifang Gao, Wei Zhou, Shuang Yang, Yanhua Liu, Yunping Luo, Tsung-Hsien Chuang, Peiqing Sun, Chenghu Liu, Rong Xiang, Chang, Antao, Chen, Yanan, Shen, Wenzhi, Gao, Ruifang, Zhou, Wei, Yang, Shuang, Liu, Yanhua, and Luo, Yunping
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LIPOPOLYSACCHARIDES , *JNK mitogen-activated protein kinases , *GALACTOSAMINE , *HEPATITIS treatment , *TUMOR necrosis factors , *LIVER cells , *APOPTOSIS , *LIVER disease treatment , *THERAPEUTICS , *METABOLISM in viruses , *ANIMAL experimentation , *BIOLOGICAL models , *CARBOHYDRATES , *CARRIER proteins , *CELL lines , *CELLULAR signal transduction , *EPITHELIAL cells , *HEPATITIS , *LIVER , *MICE , *TRANSFERASES , *VIRUSES - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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