CHARACTERIZATION OF THE PROSTANOID RECEPTORS MEDIATING INHIBITION OF PAF-INDUCED AGGREGATION OF GUINEA-PIG EOSINOPHILS

1 Prostanoids induce a wide range of biological actions which are medi ated by specific membrane-bound receptors. We have recently shown that the E-type prostaglandins, PGE(1) and PGE(2), effectively inhibit eos inophil aggregation induced by platelet-activating factor (PAF). In an attempt to determine which prostanoid receptor(s) were involved, we i nvestigated the effects of a range of selective prostanoid agonists an d antagonists on eosinophil homotypic aggregation induced by PAF. 2 Bo th PGE(1) and PGE(2) (10(-10) to 10(-6) M) induced a concentration-rel ated inhibition of the aggregation response induced by PAF. PGE(1) was more effective than PGE(2) but PGE(2) was slightly more potent than P GE(1) (approximate IC50 values for PGE(1) and PGE(2) of 1.5 x 10(-8) M and 5 x 10(-9) M, respectively). 3 The EP2-selective agonists, 11-deo xy-PGE(1), butaprost and AH13205, and the EP2/EP3-selective agonist, m isoprostol, also inhibited PAF-induced aggregation. The rank order of potency for EP2-selective agonists was 11-deoxy-PGE(1) > misoprostol > butaprost = AH13205. The protein kinase A inhibitor, KT5720 (10(-6) M ), reversed the inhibitory effects of 11-deoxy-PGE(1) (10(-6) M) and A H13205 (10(-5) M). 4 The EP1/EP3-selective agonist, sulprostone, and t he EP1-selective agonist, 17-phenyl-omega-trinor PGE(2), had no signif icant inhibitory activity when tested at concentrations up to 10(-6) M . The EP4-receptor antagonist, AH23848B, had no effect on PAF-induced aggregation and did affect the inhibitory activity of PGE(1). 5 The IP -selective agonist, cicaprost (up to 10(-6) M), and the IP/EP1-recepto r agonist, iloprost (up to 10(-5) M), had no significant effect on PAF -induced eosinophil aggregation. However, iloprost significantly augme nted the inhibitory effects of a maximally inhibitory concentration of PGE(2). 6 PGD(2) (10(-5) M) had no effect on eosinophil aggregation a nd the inhibitory activity of PGE(1) on PAF-induced eosinophil aggrega tion was not altered by the DP-selective receptor antagonist, BWA868C. 7 The results presented here suggest that the inhibition of PAF-induc ed eosinophil aggregation by prostanoids is mediated by the occupation of EP2-receptors. It is important to note that the effects of natural ly occuring prostanoids, such as PGE(2), on eosinophil aggregation occ ur at low concentrations highlighting a potential role for EP2 recepto rs in regulating eosinophil function in vivo.