THE ROLE OF RECEPTORS FOR TUMOR-NECROSIS-FACTOR-ALPHA IN THE INDUCTION OF HUMAN POLYMORPHONUCLEAR NEUTROPHIL CHEMILUMINESCENCE

Tumour necrosis factor-alpha (TNF-alpha) is a potent mediator of infla mmation, which exerts profound effects on polymorphonuclear neutrophil s (PMN). TNF-alpha binds to distinct cell surface receptors termed p55 and p75, expressed in approximately equal amounts on the PMN surface. We have studied the effects of TNF-alpha on the priming of F-Met-Leu- Phe (FMLP)-stimulated oxidative metabolism of PMN, using a luminol-enh anced chemiluminescence assay, and have examined the relative roles of PMN receptors for TNF-alpha in priming this oxidative metabolism, usi ng antibodies with p55 and p75 receptor-specific agonistic and antagon istic activities. We have obtained-the following results: (1) Antibody Htr-9 with agonistic activity at the p55 receptor mimicked the effect of TNF-alpha; however, a combination of Htr-9 and TNF-alpha did not r esult in any further increase in chemiluminescence relative to the res ponse observed with TNF-alpha alone. The p75 agonistic antibody MR2-1 actually decreased basal and FMLP-enhanced chemiluminescence. Addition ally, MR2-1 substantially inhibited the effects of both TNF-alpha itse lf and of the p55 agonist Htr-9. (2) Addition of antibodies with antag onistic activities at the p55 (antibody TBP-2) and p75 (antibody Utr-1 ) receptors resulted in a marked inhibition of the PMN response to TNF -alpha. A combination of both Utr-1 and TBP-2 was most effective at in hibiting the action of TNF. We have confirmed previously published obs ervations that TNF-alpha alone effectively stimulates the oxidative me tabolism of PMN in vitro, and that pre-incubation of PMN with TNF-alph a enhances subsequent generation of oxidative metabolites in response to FMLP. We conclude that both p55 and p75 receptors play a critical r ole in mediating the activation of PMN by TNF-alpha.