Interferon‐alpha (IFN‐α) enhances cytotoxicity in healthy volunteers and chronic hepatitis C infection mainly by the perforin pathway

Cell‐mediated cytotoxicity is exerted via perforin and Fas ligand (FasL). We have recently shown that IFN‐α up‐regulates FasL expression in T cells isolated from healthy volunteers and augments activation‐induced T cell death. Since the Fas/FasL system is implicated in the pathogenesis of hepatic failure and both molecules have been shown to be up‐regulated in hepatitis C virus (HCV) infection, we studied whether cytotoxicity via the FasL system is enhanced by IFN‐α and therefore could contribute to hepatic injury. We investigated FasL and perforin expression in peripheral blood mononuclear cells (PBMC) derived from HCV + donors by Northern analysis and soluble FasL synthesis by ELISA. Natural killer (NK) cell and cytotoxic T lymphocyte (CTL) cytotoxicity was studied by 51 Cr‐release assays. IFN‐α up‐regulates FasL mRNA and protein synthesis in mitogen‐activated PBMC of HCV + individuals, as previously found in healthy subjects. Stimulation with IFN‐α increases perforin mRNA levels in PBMC. In NK cytotoxicity assays, the enhancement of cytotoxicity by IFN‐α is mainly due to the perforin pathway, while the FasL pathway plays only a minor role. In CTL cytotoxicity experiments neither the FasL nor the perforin pathway is further enhanced by IFN‐α. Our data suggest that up‐regulation of perforin by IFN‐α results in elevated cytotoxicity, suggesting that IFN‐α might support elimination of virally infected cells via this pathway. In contrast, the major effect of IFN‐α on the Fas/FasL system might be the enhanced elimination of activated T cells as a means of finally limiting a T cell response.