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  • Title: Interferon-alpha enhances TRAIL-mediated apoptosis by up-regulating caspase-8 transcription in human hepatoma cells.
    Author: Liedtke C, Gröger N, Manns MP, Trautwein C.
    Journal: J Hepatol; 2006 Feb; 44(2):342-9. PubMed ID: 16225956.
    Abstract:
    BACKGROUND/AIMS: IFNalpha 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 IFNalpha are not completely understood. In this study, we investigated if the pro-apoptotic factor caspase-8 is a target gene of IFNalpha signalling. METHODS: Huh7 hepatoma cells were used for measuring caspase-8 promoter activity in luciferase reporter assays after IFNalpha 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: IFNalpha treatment induced caspase-8 promoter activity and mRNA expression. We identified a unique promoter element mediating the IFNalpha-dependent increase in caspase-8 transcription. Up-regulation of caspase-8 expression by IFNalpha had no impact on the rate of apoptosis per se. However, co-stimulation with IFNalpha doubled TRAIL-mediated apoptosis and enzymatic caspase-8 activity. The synergistic effect of TRAIL and IFNalpha could be blocked by inhibiting caspase-8 expression. CONCLUSIONS: We demonstrate that caspase-8 is a target gene of IFNalpha and provide evidence showing that IFNalpha treatment sensitizes cells for apoptosis via enhanced caspase-8 transcription.
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