Divergent effects of tumor necrosis factor alpha on apoptosis of human neutrophils.
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.
Central Laboratory of the Netherlands, Blood Transfusion Service Academic Medical Center, University of Amsterdam.
J M
JM
van den Berg
S
S
Weyer
J J
JJ
Weening
D
D
Roos
T W
TW
Kuijpers
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D018821:CD18 Antigens / Q000096:biosynthesis / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000096:biosynthesis / Q000502:physiology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016897:Respiratory Burst / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003513:Cycloheximide; D010100:Oxygen