Nitric oxide prevents the IFN-gamma/LPS-induced hepatotoxicity in a protein kinase G-independent manner

Although it has been well known that the role of LPS on hepatotoxicity is m ediated through TNF-alpha, the direct cytotoxic effect of LPS on IFN-gamma -primed hepatocytes has not yet been clearly demonstrated. Here, we demonst rate that the IFN-gamma -mediated death of murine embryonic liver BNL CL2 c ells is potentiated by LPS (0.5 mug/ml). In addition, an exogenous NO donor , sodium nitroprusside (SNP) significantly prevents cell death induced by I FN-gamma alone or IFN-gamma plus LPS (IFN-gamma /LPS) in a dose-dependent m anner over 25 muM. SNP significantly blocked the death of BNL CL2 cells onl y when it was added within 12 hr after treatment of IFN-gamma and IFN-gamma /LPS. The preventive effect of SNP occurred in parallel with the suppressi on of caspase 3-like protease activation. We have also demonstrated that a relatively high concentration as well as an appropriate period of exposure to NO may be critical to maintain cell viability from the cytotoxic effect of IFN-gamma and IFN-gamma /LPS. Furthermore, the preventive effect of SNP on IFN-gamma /LPS-induced cell death is mediated by a protein kinase G (PKG )-independent manner.