Divergent effects of tumor necrosis factor alpha on apoptosis of human neutrophils

J Leukoc Biol. 2001 Mar;69(3):467-73.

Abstract

Apoptosis of neutrophils is a key mechanism to control the intensity of the acute inflammatory response. Previously, the cytokine tumor necrosis factor alpha (TNF-alpha) was reported by some to have pro-apoptotic and by others to have antiapoptotic effects on neutrophils. The aim of this study was to explain these contradictory results. We found that TNF-alpha at low concentrations strongly decreased apoptosis of neutrophils. However, at higher concentrations, TNF-alpha lost its protective effects, and also reversed the protective effects of interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF). This pro-apoptotic effect of TNF-alpha was blocked by anti-CD11b and was absent in neutrophils from patients with chronic granulomatous disease, which cannot produce toxic oxygen metabolites. Under these circumstances, we found that TNF-alpha retained its anti-apoptotic effects even at high concentrations. In conclusion, the protective effects against apoptosis of IFN-gamma, GM-CSF, and TNF-alpha itself are overruled when the concentration of TNF-alpha is high enough to produce a respiratory burst. These dual, concentration-dependent effects of TNF-alpha provide an explanation for previous controversial reports and support a dominant role for TNF-alpha in neutrophil apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • CD18 Antigens / biosynthesis
  • CD18 Antigens / physiology
  • Cell Survival / drug effects
  • Cycloheximide / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Interferon-gamma / pharmacology
  • Macrophage-1 Antigen / biosynthesis
  • Macrophage-1 Antigen / physiology
  • Neutrophils / cytology
  • Neutrophils / drug effects*
  • Neutrophils / metabolism
  • Oxygen / metabolism
  • Protein Biosynthesis
  • Protein Synthesis Inhibitors / pharmacology
  • Respiratory Burst / physiology
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • CD18 Antigens
  • Macrophage-1 Antigen
  • Protein Synthesis Inhibitors
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Cycloheximide
  • Oxygen