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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