Characterization of theEPreceptor subtype that mediates the inhibitory effects of prostaglandin E2on IgE‐dependent secretion from human lung mast cells

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Abstract
Summary: Background: Prostaglandin E2(PGE2) has been shown to inhibit IgE‐dependent histamine release from human lung mast cells. This effect ofPGE2is believed to be mediated byEP2receptors. However, definitive evidence that this is the case has been lacking in the absence ofEP2‐selective antagonists. Moreover, recent evidence has suggested thatPGE2activatesEP4receptors to inhibit respiratory cell function.Objective: The aim of this study was to determine the receptor by whichPGE2inhibits human lung mast cell responses by using recently developed potent and selectiveEP2andEP4receptor antagonists alongside other establishedEPreceptor ligands.Methods: The effects of non‐selective (PGE2, misoprostol),EP2‐selective (ONO‐AE1‐259,AH13205, butaprost‐free acid) andEP4‐selective (L‐902,688,TCS251) agonists on IgE‐dependent histamine release and cyclic‐AMPgeneration in mast cells were determined. The effects ofEP2‐selective (PF‐04418948,PF‐04852946) andEP4‐selective (CJ‐042794, L‐161,982) antagonists onPGE2responses of mast cells were studied. The expression ofEPreceptor subtypes was determined byRT‐PCR.Results: Prostaglandin E2,EP2agonists andEP4agonists inhibited IgE‐dependent histamine release from mast cells.PGE2andEP2agonists, but notEP4agonists, increased cyclic‐AMPlevels in mast cells.EP4‐selective antagonists did not affect thePGE2inhibition of histamine release, whereasEP2‐selective antagonists caused rightward shifts in thePGE2concentration–response curves.RT‐PCRstudies indicated that mast cells expressedEP2andEP4receptors.Conclusions and Clinical Relevance: Although human lung mast cells may express bothEP2andEP4receptors, the principal mechanism by whichPGE2inhibits mediator release in mast cells is by activatingEP2receptors.

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