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Differential caspase-9-dependent signaling pathway between tumor necrosis factor receptor- and Fas-mediated

Motohiro Imao1, Masahito Nagaki, Motoaki Imose

  • 1First Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.

Liver International : Official Journal of the International Association for the Study of the Liver
|January 20, 2006
PubMed
Abstract

Insights

The caspase-9 inhibitor Ac-LEHD-CHO blocked tumor necrosis factor receptor (TNFR)-mediated hepatocyte apoptosis but not Fas-mediated apoptosis, suggesting distinct signaling pathways. This highlights differences in how cells initiate programmed cell death via TNFR and Fas receptors.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Apoptosis, or programmed cell death, is crucial for cellular homeostasis and is regulated by distinct signaling pathways.
  • Caspase activation is a central event in apoptosis execution.
  • Tumor necrosis factor receptor (TNFR) and Fas receptor mediate apoptosis through different cellular mechanisms.

Purpose of the Study:

  • To investigate the differential effects of a caspase-9 inhibitor on TNFR- and Fas-mediated hepatocyte apoptosis in vivo.
  • To elucidate the similarities and distinctions between TNFR and Fas signaling pathways in initiating apoptosis.

Main Methods:

  • BALB/c mice were treated with d-galactosamine/TNF-alpha or anti-Fas antibody.
  • Mice were pretreated with caspase-9 inhibitor (Ac-LEHD-CHO) or a pan-caspase inhibitor (Z-VAD-fmk).
  • Liver injury, hepatocyte apoptosis, cytochrome c release, and caspase activation were assessed.

Main Results:

  • The pan-caspase inhibitor Z-VAD-fmk protected against both TNFR- and Fas-induced apoptosis.
  • The caspase-9 inhibitor Ac-LEHD-CHO inhibited TNFR-mediated apoptosis but not Fas-mediated apoptosis.
  • Ac-LEHD-CHO blocked caspase-9 and caspase-3 activation in TNFR signaling but only caspase-9 in Fas signaling.

Conclusions:

  • TNFR-mediated hepatocyte apoptosis primarily relies on the mitochondria-dependent caspase-9 pathway.
  • Fas-mediated apoptosis involves both caspase-8 (extrinsic) and mitochondrial (intrinsic) pathways, with potential compensation if one is blocked.
  • Distinct caspase activation mechanisms underlie TNFR and Fas signaling in liver cells.

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