NITRIC OXIDE PREVENTS THE IFN-γ/LPS-INDUCED HEPATOTOXICITY IN A PROTEIN KINASE G-INDEPENDENT MANNER

Although it has been well known that the role of LPS on hepatotoxicity is mediated through TNF-alpha, the direct cytotoxic effect of LPS on IFN-gamma-primed hepatocytes has not yet been clearly demonstrated. Here, we demonstrate that the IFN-gamma-mediated death of murine embryonic liver BNL CL2 cells is potentiated by LPS (0.5 microg/ml). In addition, an exogenous NO donor, sodium nitroprusside (SNP) significantly prevents cell death induced by IFN-gamma alone or IFN-gamma plus LPS (IFN-gamma/LPS) in a dose-dependent manner over 25 microM. SNP significantly blocked the death of BNL CL2 cells only 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 suppression 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.