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TRAIL receptor-mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and

Nadia Corazza1, Sabine Jakob, Corinne Schaer

  • 1Division of Immunopathology, Institute of Pathology, University of Bern, Bern, Switzerland.

The Journal of Clinical Investigation
|September 7, 2006
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) amplifies Fas-induced liver cell death and damage. This suggests potential risks of liver damage and lethality with TRAIL-based cancer therapies.

Area of Science:

  • Immunology
  • Cell Biology
  • Hepatology

Background:

  • TNF-related apoptosis-inducing ligand (TRAIL) induces tumor cell death and synergizes with chemotherapy.
  • The role of TRAIL in normal cells and potential tissue damage from TRAIL-based therapies are poorly understood.

Purpose of the Study:

  • To investigate the role of TRAIL in Fas-induced hepatocyte apoptosis and liver damage.
  • To determine if TRAIL influences liver injury and lethality in vivo.

Main Methods:

  • Investigated TRAIL's role in Fas-induced hepatocyte apoptosis using isolated murine hepatocytes.
  • Utilized in vivo models with anti-Fas antibodies, TRAIL-deficient mice, Bim-deficient mice, and JNK inhibitors to assess liver damage and lethality.

Main Results:

  • TRAIL alone did not induce apoptosis in isolated hepatocytes but significantly amplified Fas-induced cell death.
  • Endogenous TRAIL critically regulated anti-Fas antibody-induced hepatocyte apoptosis, liver damage, and lethality in vivo.
  • TRAIL enhanced Fas-induced apoptosis via JNK and Bim activation; TRAIL/Bim deficiency or JNK inhibition protected against liver damage.

Conclusions:

  • TRAIL and Bim are crucial modulators of hepatocyte apoptosis.
  • TRAIL-based cancer therapies may carry a risk of liver damage and lethality.

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