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Characterization of the EP receptor subtype that mediates the inhibitory effects of prostaglandin E 2 on IgE‐dependent secretion from human lung mast cells
Author(s) -
Kay L. J.,
Gilbert M.,
Pullen N.,
Skerratt S.,
Farrington J.,
Seward E. P.,
Peachell P. T.
Publication year - 2013
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12142
Subject(s) - histamine , prostaglandin d2 , receptor , mast cell , prostaglandin e2 receptor , prostaglandin e , immunoglobulin e , prostaglandin , histamine h4 receptor , chemistry , medicine , endocrinology , pharmacology , agonist , biology , histamine h2 receptor , immunology , biochemistry , antagonist , antibody
Summary Background Prostaglandin E 2 ( PGE 2 ) has been shown to inhibit IgE‐dependent histamine release from human lung mast cells. This effect of PGE 2 is believed to be mediated by EP 2 receptors. However, definitive evidence that this is the case has been lacking in the absence of EP 2 ‐selective antagonists. Moreover, recent evidence has suggested that PGE 2 activates EP 4 receptors to inhibit respiratory cell function. Objective The aim of this study was to determine the receptor by which PGE 2 inhibits human lung mast cell responses by using recently developed potent and selective EP 2 and EP 4 receptor antagonists alongside other established EP receptor ligands. Methods The effects of non‐selective ( PGE 2 , misoprostol), EP 2 ‐selective ( ONO ‐ AE 1‐259, AH 13205, butaprost‐free acid) and EP 4 ‐selective (L‐902,688, TCS 251) agonists on IgE‐dependent histamine release and cyclic‐ AMP generation in mast cells were determined. The effects of EP 2 ‐selective ( PF ‐04418948, PF ‐04852946) and EP 4 ‐selective ( CJ ‐042794, L‐161,982) antagonists on PGE 2 responses of mast cells were studied. The expression of EP receptor subtypes was determined by RT ‐ PCR . Results Prostaglandin E 2 , EP 2 agonists and EP 4 agonists inhibited IgE‐dependent histamine release from mast cells. PGE 2 and EP 2 agonists, but not EP 4 agonists, increased cyclic‐ AMP levels in mast cells. EP 4 ‐selective antagonists did not affect the PGE 2 inhibition of histamine release, whereas EP 2 ‐selective antagonists caused rightward shifts in the PGE 2 concentration–response curves. RT ‐ PCR studies indicated that mast cells expressed EP 2 and EP 4 receptors. Conclusions and Clinical Relevance Although human lung mast cells may express both EP 2 and EP 4 receptors, the principal mechanism by which PGE 2 inhibits mediator release in mast cells is by activating EP 2 receptors.