Alkyl-PAF and acyl-paf induced human neutrophil stimulation via low and/or high affinity PAF receptors, respectively

Two components of PMN priming by alkyl-PAF for enhanced FMLP and rC5a 02" production were identified. Component A priming was induced by low concentrations of alkyl-PAF (10 pM-1 nM) and component B by high concentrations (1 nM-1 }lM). Component A priming did not decay with time after PMN stimulation with alkyl-PAF while component B rapidly decayed within 5-10 min. Whereas component A priming was completely inhibited by pretreatment of PMN with WEB 2086 (1-10 (iM), component B priming was unaffected by this potent PAF receptor antagonist. Acyl-PAF (1 nM-1 (iM) induced only component A PMN priming. These observations suggest that components A and B priming are modulated through at least two effector pathways that are triggered via high and low affinity PAF receptors, respectively; and, while alkyl-PAF effectively interacts with both receptors, acyl-PAF and WEB 2086 preferentially interact with high affinity PAF receptors. Concentration-response characteristics and WEB 2086 sensitivity of alkyl-PAF induced PMN chemotaxis, homotypic aggregation, U2" production, and azurophilic and specific granule enzyme secretion support the notion that occupancy of both high and low affinity PAF receptors is required to maximize these responses which are not induced by acyl-PAF (<1 |im). On the other hand, occupancy of only high affinity receptors by either alkyl-PAF or acyl-PAF effectively induces the release of intracellular Ca2+, component A priming, CDllb up-regulation and the secretion of gelatinase. These studies provide an explanation as to why alkvl-PAF and acvl-PAF are complete and partial PMN aeonists. respectively.