Prostaglandin E2 activates EP2 receptors to inhibit human lung mast cell degranulation

1 The prostanoid, PGE(2), is known to inhibit human lung mast cell activity. The aim of the present study was to characterize the EP receptor that mediates this effect. 2 PGE(2) (pEC(50), 5.8 +/- 0.1) inhibited the IgE-mediated release of histamine from mast cells in a concentration-dependent manner. Alternative EP receptor agonists were studied. The EP2-selective agonist, butaprost (pEC(50), 5.2 +/- 0.2), was an effective inhibitor of mediator release whereas the EP1/ EP3 receptor agonist, sulprostone, and the EP1-selective agonist, 17-phenyl-trinor-PGE(2), were ineffective. 3 The DP agonist PGD(2), the FP agonist PGF(2 alpha), the IP agonist iloprost and the TP agonist U-46619 were ineffective inhibitors of IgE-mediated histamine release from mast cells. 4 PGE(2) induced a concentration-dependent increase in intracellular cAMP levels in mast cells. 5 The effects of the EP1/ EP2 receptor antagonist, AH6809, and the EP4 receptor antagonist, AH23848, on the PGE(2)-mediated inhibition of histamine release were determined. AH6809 (pK(B), 5.6 +/- 0.1) caused a modest rightward shift in the PGE(2) concentration - response curve, whereas AH23848 was ineffective. 6 Long-term ( 24 h) incubation of mast cells with either PGE(2) or butaprost (EP2 agonist), but not sulprostone (EP1/EP3 agonist), caused a significant reduction in the subsequent ability of PGE(2) to inhibit histamine release. 7 Collectively, these data suggest that PGE(2) mediates effects on human lung mast cells by interacting with EP2 receptors.