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Caspase inhibitors induce a switch from apoptotic to proinflammatory signaling in CD95-stimulated T lymphocytes

Carsten Scheller1, Sieghart Sopper, Christina Ehrhardt

  • 1Institut für Virologie und Immunbiologie, Julius-Maximilians-Universität, Würzburg, Germany. scheller@vim.uni-wuerzburg.de

European Journal of Immunology
|September 11, 2002
PubMed

Insights

Blocking CD95-induced apoptosis with caspase inhibitors triggers necrosis and pro-inflammatory cytokine release in T lymphocytes. Caspases normally suppress this inflammatory pathway during programmed cell death.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • CD95 (Fas receptor) is a key mediator of apoptosis, inducing programmed cell death via caspase activation.
  • Caspase activity is crucial for apoptosis, but its role in regulating other cellular responses, like inflammation, is less understood.

Purpose of the Study:

  • To investigate the cellular consequences of blocking CD95-mediated apoptosis in T lymphocytes.
  • To elucidate the signaling pathways involved in CD95-induced inflammation when apoptosis is inhibited.

Main Methods:

  • Primary T lymphocytes and A3.01 T cells were stimulated via CD95.
  • Caspase activity was inhibited using specific peptidic inhibitors (z-VAD-FMK, Ac-IETD-FMK).
  • Cytokine expression (TNF-alpha, IFN-gamma, GM-CSF) and activation of signaling pathways (MEK/ERK, p38, NF-kappaB) were analyzed.

Main Results:

  • Inhibition of caspases during CD95 stimulation led to necrosis instead of apoptosis.
  • Necrosis induced by CD95 stimulation in the presence of caspase inhibitors resulted in the expression of pro-inflammatory cytokines (TNF-alpha, IFN-gamma, GM-CSF).
  • CD95-mediated pro-inflammatory signaling involved MEK/ERK, p38, and NF-kappaB pathways, and this signaling was suppressed by active caspases.

Conclusions:

  • Caspases play a dual role: mediating apoptosis and actively suppressing pro-inflammatory signaling during CD95 activation.
  • Blocking apoptosis via caspase inhibition redirects CD95 signaling towards necrosis and inflammation.
  • These findings offer insights into novel therapeutic strategies targeting inflammatory responses in T cells.

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