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Caspase activation during hepatocyte apoptosis induced by tumor necrosis factor-alpha in galactosamine-sensitized

Y Osawa1, Y Banno, M Nagaki

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

Liver
|October 9, 2001
PubMed
Abstract

Insights

Tumor necrosis factor-alpha (TNF-alpha) induces hepatocyte apoptosis via cytochrome c release and caspase-9 activation. Ceramide accumulation precedes these events, suggesting its role in TNF-alpha-induced liver cell death.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Toxicology

Background:

  • Hepatocyte apoptosis is a critical process in liver injury.
  • Tumor necrosis factor-alpha (TNF-alpha) can induce apoptosis in hepatocytes, but the precise mechanism remains unclear.
  • D-galactosamine (GalN) sensitizes mice to TNF-alpha-induced liver injury.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying TNF-alpha-induced hepatocyte apoptosis.
  • To investigate the roles of caspase activation and ceramide formation in this process.

Main Methods:

  • BALB/c mice were treated with GalN and TNF-alpha.
  • Western blotting was used to analyze cytochrome c release and procaspase processing.
  • Caspase activities were measured using chromogenic substrates.
  • Ceramide levels were quantified using diacylglycerol kinase assay.

Main Results:

  • Hepatocyte apoptosis was observed only in mice treated with both GalN and TNF-alpha.
  • Cytochrome c release and activation of caspase-9 and caspase-3 were detected in the livers of GalN/TNF-alpha-treated mice.
  • Ceramide accumulation preceded cytochrome c release and caspase activation.
  • Caspase-3 activation was dependent on caspase-9, not caspase-8 or -2.

Conclusions:

  • Cytochrome c release and caspase-9 activation are essential for TNF-alpha-induced hepatocyte apoptosis.
  • Caspase-8 and caspase-2 play minimal roles in this pathway.
  • Ceramide accumulation is implicated in the mechanism of TNF-alpha-induced hepatocyte apoptosis.

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