c-Myc partially mediates IFNgamma-induced apoptosis in the primary hepatocyte.

Interferon-gamma (IFNgamma) is a central component of the complex cytokine and inflammatory response that contributes to liver cell injury in hepatitis. We report that in the primary hepatocyte IFNgamma synergizes with the mechanistically distinct apoptotic stimuli CD95, tumour necrosis factor-alpha (TNFalpha) and UV-irradiation. For the first time in primary hepatocytes, we show that IFNgamma-mediated apoptotic signalling requires the cell surface interaction of CD95 and its ligand, and we demonstrate that IFNgamma induces soluble CD95 ligand release from hepatocyte monolayers. Utilizing c-myc phosphorothioate antisense fragments, we suppresses hepatocyte apoptosis induced by IFNgamma. In summary, we identify apoptotic pathways that contribute to IFNgamma-mediated cell death. The hepatocellular response to IFNgamma signalling can be modulated by cytokines and by the interruption of CD95 interaction with its ligand. We present evidence to suggest that c-myc contributes to IFNgamma signalling.

The effect of IFNgamma on the hepatocyte: cell cycle and apoptosis.

The inflammatory cytokine interferon gamma (IFNgamma) can cause cell cycle arrest and apoptosis in the hepatocyte. Primarily these processes are protective but in chronic liver disease oncogenic mutations may prosper. IFNgamma signalling is discussed showing how p53 is induced to cause cell cycle arrest. While caspases are are known to be responsible for IFNgamma induced apoptosis, how they are activated is unclear. Potential mechanisms are reviewed.