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 mediated by specific membrane-bound receptors. We have recently shown that the E-type prostaglandins, PGE(1) and PGE(2), effectively inhibit eosinophil aggregation induced by platelet-activating factor (PAF). In an attempt to determine which prostanoid receptor(s) were involved, we investigated the effects of a range of selective prostanoid agonists and antagonists on eosinophil homotypic aggregation induced by PAF. 2 Both PGE(1) and PGE(2) (10(-10) to 10(-6) M) induced a concentration-related inhibition of the aggregation response induced by PAF. PGE(1) was more effective than PGE(2) but PGE(2) was slightly more potent than PGE(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-deoxy-PGE(1), butaprost and AH13205, and the EP2/EP3-selective agonist, misoprostol, 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 AH13205 (10(-5) M). 4 The EP1/EP3-selective agonist, sulprostone, and the EP1-selective agonist, 17-phenyl-omega-trinor PGE(2), had no significant 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-receptor agonist, iloprost (up to 10(-5) M), had no significant effect on PAF-induced eosinophil aggregation. However, iloprost significantly augmented the inhibitory effects of a maximally inhibitory concentration of PGE(2). 6 PGD(2) (10(-5) M) had no effect on eosinophil aggregation and the inhibitory activity of PGE(1) on PAF-induced eosinophil aggregation was not altered by the DP-selective receptor antagonist, BWA868C. 7 The results presented here suggest that the inhibition of PAF-induced eosinophil aggregation by prostanoids is mediated by the occupation of EP2-receptors. It is important to note that the effects of naturally occuring prostanoids, such as PGE(2), on eosinophil aggregation occur at low concentrations highlighting a potential role for EP2 receptors in regulating eosinophil function in vivo.