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-
(IFN-) 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-, 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--deficient mice indicate that IFN- 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-- and IFN- plus tumor necrosis factor-
-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.
