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Am J Physiol Gastrointest Liver Physiol (June 19, 2003). doi:10.1152/ajpgi.00224.2003
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Submitted on May 13, 2003
Accepted on June 10, 2003

STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury

Won-Ho Kim1, Feng Hong1, Svetlana Radaeva1, Barbara Jaruga1, Saijun Fan2, and Bin Gao1*

1 Section on Liver Biology, National Institutes of Health,National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
2 Laboratory of Molecular Oncology, Georgetown University Medical Center, Washington DC, Washington DC, USA

* To whom correspondence should be addressed. E-mail: bgao{at}mail.nih.gov.

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 signal transducer and activator of transcription factor-1 (STAT1), a key-signaling molecule for IFN-{gamma}, in a model of murine hepatitis induced by 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} plus tumor necrosis factor-{alpha}-induced cell death, whereas Hep3B cells overexpression of 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.




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