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

Christian Liedtke1, Nadine Gröger, Michael P Manns

  • 1Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. chrliedtke@aol.com

Journal of Hepatology
|October 18, 2005
PubMed
Abstract

Insights

Interferon-alpha (IFNalpha) upregulates the pro-apoptotic factor caspase-8, enhancing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. This reveals a novel mechanism for IFNalpha

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • Interferon-alpha (IFNalpha) is an approved treatment for chronic hepatitis B and C infections and has demonstrated efficacy in tumor therapy.
  • The precise mechanisms underlying IFNalpha's antiviral and antitumor effects remain incompletely understood.
  • Investigating IFNalpha's molecular targets is crucial for understanding its therapeutic potential.

Purpose of the Study:

  • To determine if the pro-apoptotic factor caspase-8 is a direct target gene of IFNalpha signaling.
  • To elucidate the role of caspase-8 in IFNalpha-mediated cellular responses.
  • To identify the specific promoter elements involved in IFNalpha-induced caspase-8 transcription.

Main Methods:

  • Luciferase reporter assays were used to measure caspase-8 promoter activity in Huh7 hepatoma cells following IFNalpha stimulation.
  • Caspase-8 expression levels were assessed using RT-PCR, immunoblotting, and enzymatic activity assays.
  • Gelshift assays and site-directed mutagenesis identified functional caspase-8 promoter elements, while siRNA was used to inhibit caspase-8 expression.

Main Results:

  • IFNalpha stimulation significantly increased caspase-8 promoter activity and mRNA expression.
  • A unique promoter element was identified that mediates the IFNalpha-dependent transcriptional upregulation of caspase-8.
  • While IFNalpha alone did not affect apoptosis rates, it synergistically enhanced TRAIL-mediated apoptosis and caspase-8 activity, an effect blocked by caspase-8 inhibition.

Conclusions:

  • Caspase-8 is confirmed as a direct target gene of IFNalpha signaling.
  • IFNalpha treatment sensitizes cells to apoptosis by enhancing caspase-8 transcription.
  • This study provides a mechanistic link between IFNalpha and apoptosis induction, relevant for its therapeutic applications.

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