TNF-alpha in vivo stimulates apoptosis in fibroblasts through caspase-8 activation and modulates the expression of pro-apoptotic genes

J Cell Physiol. 2004 Dec;201(3):341-8. doi: 10.1002/jcp.20067.


Apoptosis of matrix producing cells is common among many inflammatory diseases. The goal of the present study was to examine the apoptotic effects of tumor necrosis factor-alpha (TNF-alpha) on fibroblastic cells in vivo and to investigate the role of different caspases in this process. This was accomplished in vivo by subcutaneous injection of TNF-alpha in mice. The direct effects of TNF-alpha on fibroblast apoptosis were studied in vitro with normal diploid human fibroblasts. The results indicate that TNF-alpha in vivo induces apoptosis of fibroblasts. By RNase protection assay, we demonstrated that TNF-alpha stimulates expression of 12 apoptotic genes. Fluorometric studies demonstrated that TNF-alpha in vivo predominantly increased caspase-8 and -3 activity and by use of specific inhibitors, the activation of caspase-3 was shown to be initiated by caspase-8 with only a minor contribution from caspase-9. Thus, TNF-alpha acts to modulate the expression of many genes that favors apoptosis of fibroblastic cells, which is dependent mostly upon signaling through caspase-8.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / physiology
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / genetics*
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Line
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts
  • Gene Expression Regulation / drug effects*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Tumor Necrosis Factor-alpha
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Casp3 protein, mouse
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases