Characterization of the EP receptor subtype that mediates the inhibitory effects of prostaglandin E2 on IgE-dependent secretion from human lung mast cells
Characterization of the EP receptor subtype that mediates the inhibitory effects of prostaglandin E2 on IgE-dependent secretion from human lung mast cells
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DOI：
10.1111/cea.12142
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发表时间：
2013-07-01
影响因子：
6.1
通讯作者：
Peachell, P. T.
中科院分区：
文献类型：
--
作者：
Kay, L. J.;Gilbert, M.;Peachell, P. T.
前列腺素E2（PGE 2）已被证明能抑制IgE依赖性组胺从人肺肥大细胞释放。PGE 2的这种作用被认为是由EP 2受体介导的。然而，在缺乏EP 2选择性拮抗剂的情况下，缺乏证明这种情况的确切证据。此外，最近的证据表明，PGE 2激活EP 4受体，抑制呼吸细胞功能。目的研究前列腺素E2（PGE 2）抑制人肺肥大细胞（肥大细胞）反应的受体，并与EP受体配体一起应用。方法观察非选择性（PGE 2，米索前列醇）、EP 2选择性（ONO AE 1 -259，AH 13205，布他前列素游离酸）和EP 4选择性（L-902，688，TCS 251）激动剂对肥大细胞IgE依赖性组胺释放和cAMP生成的影响。研究了EP 2选择性（PF-04418948，PF-04852946）和EP 4选择性（CJ-042794，L-161，982）拮抗剂对肥大细胞PGE 2反应的影响。采用RT-PCR方法检测EP受体亚型的表达。结果前列腺素E2、EP 2激动剂和EP 4激动剂均能抑制肥大细胞释放IgE依赖性组胺。PGE 2和EP 2激动剂，但不是EP 4激动剂，增加肥大细胞中的环AMP水平。EP 4选择性拮抗剂不影响PGE 2抑制组胺释放，而EP 2选择性拮抗剂引起PGE 2浓度-反应曲线的显著偏移。RT-PCR结果显示肥大细胞表达EP 2和EP 4受体。结论和临床意义虽然人肺肥大细胞可能同时表达EP 2和EP 4受体，但PGE 2抑制肥大细胞中介质释放的主要机制是通过激活EP 2受体。
Background Prostaglandin E2 (PGE2) has been shown to inhibit IgE-dependent histamine release from human lung mast cells. This effect of PGE2 is believed to be mediated by EP2 receptors. However, definitive evidence that this is the case has been lacking in the absence of EP2-selective antagonists. Moreover, recent evidence has suggested that PGE2 activates EP4 receptors to inhibit respiratory cell function. Objective The aim of this study was to determine the receptor by which PGE2 inhibits human lung mast cell responses by using recently developed potent and selective EP2 and EP4 receptor antagonists alongside other established EP receptor ligands. Methods The effects of non-selective (PGE2, misoprostol), EP2-selective (ONO-AE1-259, AH13205, butaprost-free acid) and EP4-selective (L-902,688, TCS251) agonists on IgE-dependent histamine release and cyclic-AMP generation in mast cells were determined. The effects of EP2-selective (PF-04418948, PF-04852946) and EP4-selective (CJ-042794, L-161,982) antagonists on PGE2 responses of mast cells were studied. The expression of EP receptor subtypes was determined by RT-PCR. Results Prostaglandin E2, EP2 agonists and EP4 agonists inhibited IgE-dependent histamine release from mast cells. PGE2 and EP2 agonists, but not EP4 agonists, increased cyclic-AMP levels in mast cells. EP4-selective antagonists did not affect the PGE2 inhibition of histamine release, whereas EP2-selective antagonists caused rightward shifts in the PGE2 concentration-response curves. RT-PCR studies indicated that mast cells expressed EP2 and EP4 receptors. Conclusions and Clinical Relevance Although human lung mast cells may express both EP2 and EP4 receptors, the principal mechanism by which PGE2 inhibits mediator release in mast cells is by activating EP2 receptors.