Growth factor attenuation of IFNγ‐mediated hepatocyte apoptosis requires p21^waf−1

Abstract

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).

Regulation of hepatocyte fate by interferon-γ

“…HGF is a multifunctional cytokine that has a protective effect against liver injury and stimulates hepatocyte proliferation during liver regeneration [48, 49]. The mechanism by which HGF protects against IFN-γ-mediated apoptosis has been attributed to a growth factor-induced survival signal that requires p21 [50], although other mechanisms may exist. Understanding how growth factors and cytokines influence hepatocyte susceptibility to IFN-γ-mediated apoptosis will provide insight into mechanisms of IFN-γ cytotoxicity under both physiological and pathological conditions.…”

c‐Myc partially mediates IFNγ‐induced apoptosis in the primary hepatocyte

“…Interferon‐gamma induces primary hepatocyte apoptosis in the context of serum deprivation (McCullough et al. 2006).…”

“…Apoptosis induced by UV‐irradiation is not associated with soluble CD95 release, suggesting that this is an IFN γ ‐specific effect. Thus, IFN γ ‐induced apoptosis in the primary hepatocyte exhibits similar characteristics to apoptosis induced by c‐myc overexpression including apoptosis induction in association with serum deprivation (McCullough et al. 2006), synergy with mechanistically distinct apoptotic stimuli, and the requirement of CD95/CD95L interaction.…”

“…The timing of sCD95L production is noteworthy. Ligand detection is maximal between 24 and 48 h, although hepatocyte apoptosis is not detected until 72 h (McCullough et al. 2006).…”

“…We have previously shown that IFN γ induces primary hepatocyte apoptosis in the context of serum deprivation and that specific growth factors suppress the apoptotic response (McCullough et al. 2006).…”