STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury.
Interferon-gamma (IFN-gamma) has been implicated in liver damage in animal models and chronic hepatitis C infection; however, the underlying mechanism is not clear. Here we examined the role of STAT1, a key signaling molecule for IFN-gamma, in a model of murine hepatitis induced by the injection of LPS/D-galactosamine and in human hepatoma Hep3B cells. STAT1 is rapidly activated and highly induced after injection of LPS/D-galactosamine. Both overexpression of STAT1 and hepatocellular damage are located in the same pericentral region. Disruption of the STAT1 gene abolishes LPS/D-galactosamine-induced liver injury. Studies from IFN-gamma-deficient mice indicate that IFN-gamma is the major cytokine responsible for activation and hyperexpression of STAT1 in LPS/D-galactosamine-induced hepatitis. Hep3B cells overexpressing dominant negative STAT1 are resistant to IFN-gamma and IFN-gamma + TNF-alpha-induced cell death, whereas Hep3B cells overexpressing wild-type STAT1 are more susceptible to cell death. Taken together, these findings suggest that STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury.
Kim
Won-Ho
WH
Section on Liver Biology, National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health, Bethesda, MD 20892, USA.
Hong
Feng
F
Radaeva
Svetlana
S
Jaruga
Barbara
B
Fan
Saijun
S
Gao
Bin
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D005688:Galactosamine / Q000494:pharmacology*; D022781:Hepatocytes / Q000737:chemistry / Q000648:ultrastructure; D007371:Interferon-gamma / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008107:Liver Diseases / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D019000:Phosphotyrosine; D005688:Galactosamine; D007371:Interferon-gamma