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Endotoxin reduces CD95-induced neutrophil apoptosis by cIAP-2-mediated caspase-3 degradation

Ladislav Mica1, Luc Härter, Otmar Trentz

  • 1Division of Trauma Surgery, University Hospital Zurich, Zurich, Switzerland.

Journal of the American College of Surgeons
|September 30, 2004
PubMed
Abstract

Insights

Endotoxins reduce neutrophil apoptosis in sepsis by increasing cIAP-2 and promoting caspase-3 degradation via the proteasome. This mechanism explains reduced programmed cell death in neutrophils during sepsis.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Reduced neutrophil apoptosis is implicated in systemic inflammatory response syndrome, sepsis, and multiple organ dysfunction syndrome.
  • Intracellular inhibitor of apoptosis proteins (IAPs) can inhibit activated caspase-3.
  • This study investigates the dynamics of cIAP-2 mRNA and caspase-3 protein in neutrophils during sepsis.

Purpose of the Study:

  • To investigate the role of cIAP-2 mRNA and caspase-3 protein turnover in neutrophil apoptosis during sepsis.
  • To determine the effect of lipopolysaccharide (LPS) and proteasome inhibition on neutrophil apoptosis and caspase-3 activation.

Main Methods:

  • Neutrophils were treated with LPS, a proteasome inhibitor, and/or CD95 antibody.
  • Apoptosis was assessed using Annexin-V and propidium iodide staining via flow cytometry.
  • Caspase-3 activity, ubiquitinated caspase-3, cIAP-2 protein, and cIAP-2 mRNA levels were measured.

Main Results:

  • LPS induced cIAP-2 mRNA and protein expression within 2 hours.
  • LPS significantly reduced spontaneous and CD95-induced apoptosis and caspase-3 activation.
  • Proteasome inhibition abolished the antiapoptotic effects of LPS and prevented caspase-3 degradation.

Conclusions:

  • Endotoxin-induced cIAP-2 expression and proteasome-mediated degradation of caspase-3 contribute to reduced neutrophil apoptosis in sepsis.
  • These findings elucidate a key mechanism underlying neutrophil survival in sepsis.

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