Prostaglandin E2 activates EP2 receptors to inhibit human lung mast cell degranulation.
The prostanoid, PGE2, 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. PGE2 (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 (pEC50, 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-PGE2, were ineffective. The DP agonist PGD2, the FP agonist PGF(2alpha), the IP agonist iloprost and the TP agonist U-46619 were ineffective inhibitors of IgE-mediated histamine release from mast cells. PGE2 induced a concentration-dependent increase in intracellular cAMP levels in mast cells. The effects of the EP1/EP2 receptor antagonist, AH6809, and the EP4 receptor antagonist, AH23848, on the PGE2-mediated inhibition of histamine release were determined. AH6809 (pK(B), 5.6+/-0.1) caused a modest rightward shift in the PGE2 concentration-response curve, whereas AH23848 was ineffective. Long-term (24 h) incubation of mast cells with either PGE2 or butaprost (EP2 agonist), but not sulprostone (EP1/EP3 agonist), caused a significant reduction in the subsequent ability of PGE2 to inhibit histamine release. Collectively, these data suggest that PGE2 mediates effects on human lung mast cells by interacting with EP2 receptors.
Kay
Linda J
LJ
Molecular Pharmacology, University of Sheffield, The Royal Hallamshire Hospital (Floor M), Glossop Road, Sheffield, S Yorks S10 2JF.
Yeo
Wilfred W
WW
Peachell
Peter T
PT
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D002021:Buffers; D015550:Cell Degranulation / Q000187:drug effects*; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000166:cytology* / Q000187:drug effects; D008297:Male; D008407:Mast Cells / Q000187:drug effects*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype
D000318:Adrenergic beta-Agonists; D002021:Buffers; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; D011448:Prostaglandin Antagonists; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000242:Cyclic AMP; D015232:Dinoprostone; D007545:Isoproterenol; D004121:Dimethyl Sulfoxide