Interferon-α enhances TRAIL-mediated apoptosis by up-regulating caspase-8 transcription in human hepatoma cells

Background/Aims IFNα is an approved treatment option for patients chronically infected with the hepatitis B and C viruses. Additionally, there is an indication for tumor therapy. The exact mechanisms underlying the antiviral and antitumor effects of IFNα are not completely understood. In this study, we investigated if the pro-apoptotic factor caspase-8 is a target gene of IFNα signalling. Methods Huh7 hepatoma cells were used for measuring caspase-8 promoter activity in luciferase reporter assays after IFNα stimulation. Caspase-8 expression was monitored by RT-PCR, immunoblotting and measurement of enzymatic activity. Functional caspase-8 promoter elements were identified in gelshift assays and by site directed mutagenesis. Caspase-8 was inhibited using siRNA. Results IFNα treatment induced caspase-8 promoter activity and mRNA expression. We identified a unique promoter element mediating the IFNα-dependent increase in caspase-8 transcription. Up-regulation of caspase-8 expression by IFNα had no impact on the rate of apoptosis per se. However, co-stimulation with IFNα doubled TRAIL-mediated apoptosis and enzymatic caspase-8 activity. The synergistic effect of TRAIL and IFNα could be blocked by inhibiting caspase-8 expression. Conclusions We demonstrate that caspase-8 is a target gene of IFNα and provide evidence showing that IFNα treatment sensitizes cells for apoptosis via enhanced caspase-8 transcription