Fas (CD95)- and tumor necrosis factor-mediated apoptosis in liver endothelial cells: role of caspase-3 and the p38 MAPK

Microvasc Res. 2002 Jan;63(1):10-8. doi: 10.1006/mvre.2001.2360.


Recently, we showed that TNF enhances the susceptibility of endothelial cells from murine liver sinusoids (LEC) to Fas-mediated apoptosis, suggesting that signals transduced by Fas and TNF receptors may synergistically increase intracellular death signals in these cells. In this work we evaluated whether caspase-3 and p38 are involved in LEC apoptosis induced by Fas and TNF. Here we show that LEC treated with Fas agonist (Jo2 mAb at 0.1 microg/ml) and TNF had a greater caspase-3 activity (twofold increase) than cells treated with each factor alone. There was a strong correlation between caspase-3 activity and cell killing induced by Jo2/TNF, indicating that this caspase plays a critical role in this process. Likewise, there was a significant increase in caspase-8 activity in LEC treated with Jo2 and TNF, compared with untreated cells or cells treated with each factor alone. Apoptosis of LEC induced by Jo2/TNF was partially reversed by SB203580, a p38 inhibitor, suggesting that p38 is involved in apoptosis of these cells. To our knowledge, this is the first report that apoptosis induced by Fas/TNF in LEC is associated with coactivation of both caspase-3 and p38. Potentially, both caspase-3 and p38 may be of great importance in endothelial cell pathology as molecular targets for preventing vascular damage due to endothelial cell apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 3
  • Caspases / biosynthesis
  • Caspases / physiology*
  • Dose-Response Relationship, Drug
  • Endothelium / cytology*
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Imidazoles / pharmacology
  • Liver / cytology*
  • Liver / metabolism
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinases / physiology*
  • Pyridines / pharmacology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction
  • Time Factors
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • fas Receptor / biosynthesis*
  • p38 Mitogen-Activated Protein Kinases


  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • SB 203580