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- Title
Ifit1 Protects Against Lipopolysaccharide and D-galactosamine-Induced Fatal Hepatitis by Inhibiting Activation of the JNK Pathway.
- Authors
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; Luo, Yunping
- 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.
- Subjects
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
- Publication
Journal of Infectious Diseases, 2015, Vol 212, Issue 9, p1509
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiv221