Promotion of neutrophil apoptosis by TNF-alpha

We examined the ability of TNF-alpha to modulate human neutrophil apoptosis . Neutrophils cultured,vith TNF-ru alone undergo a low but significant incr ease in the number of apoptotic cells. More interestingly, when neutrophils ,were pretreated with TNF-alpha for 1-2 min at 37 degreesC and then were ex posed to a variety of agents such as immobilized IgG, IgG-coated erythrocyt es, complement-treated erythrocytes, zymosan, PMA, zymosan-activated serum, fMLP, Escherichia coli, and GM-CSF for 3 h at 37 degreesC, a marked stimul ation of apoptosis was observed. Similar results were obtained in neutrophi ls pretreated with TNF-alpha for 30 min, 1 h, 3 h, and 18 h. Dose-dependent studies showed that TNF-alpha enhances neutrophil apoptosis at concentrati ons ranging from 1 to 100 ng/ml. In contrast to the observations made in ne utrophils pretreated with TNF-alpha, there was no stimulation of apoptosis when TNF-alpha was added to neutrophils previously activated by conventiona l agonists. Experiments performed to establish the mechanism through which TNF-alpha promotes neutrophil apoptosis showed that neither reactive oxygen intermediates nor the Fas/Fas Ligand system appear to be involved. Our res ults suggest that TNF-alpha plays a critical role in the control of neutrop hil survival by virtue of its ability to induce an apoptotic death program which could be triggered by a variety of conventional agonists.