Growth factor attenuation of IFNgamma-mediated hepatocyte apoptosis requires p21waf-1

Interferon gamma (IFNgamma) is an important mediator of inflammatory liver damage as part of a complex cytokine network. In vitro, IFNgamma induces hepatocyte apoptosis. We hypothesized that the hepatocyte response to IFN signalling is context-dependent, and that specific growth factors, via phosphatidylinositol 3 kinase (PI(3)K) and protein kinase B/Akt signalling pathways, confer a cytoprotective effect. We established an in vitro model of IFNgamma-mediated primary hepatocyte injury. We show that epidermal growth factor (EGF) and hepatocyte growth factor (HGF) attenuate the IFNgamma-induced hepatocyte apoptosis. IRF-1, but not p53, is required for IFNgamma-mediated apoptosis. The loss of p21(waf-1) not only sensitizes the hepatocyte to IFNgamma-mediated injury but is required for survival factor mediated cytoprotection. We show that the PI(3)K inhibitor, LY294002, partially inhibits the apoptotic response of the hepatocyte to IFNgamma. In summary, we present evidence that a component of pro-apoptotic IFNgamma signalling in the primary hepatocyte occurs via the PI(3)K pathway. We show that the hepatocyte response to IFNgamma is modulated by external survival factors and that this survival signalling requires p21(waf-1).