EP2 and EP4 receptor antagonists: Impact on cytokine production and 2-adrenergic receptor desensitization in human airway smooth muscle
EP2 and EP4 receptor antagonists: Impact on cytokine production and 2-adrenergic receptor desensitization in human airway smooth muscle
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DOI：
10.1002/jcp.27938
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发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Ammit, Alaina J.
中科院分区：
文献类型：
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作者：
Bradbury, Peta;Rumzhum, Nowshin N.;Ammit, Alaina J.
前列腺素E-2（PGE（2））是一种关键的前列腺素，已知在慢性呼吸道疾病的背景下具有促炎和抗炎作用。我们推测，这些相反的效果可能是不同的前列腺素E（EP）受体介导的信号通路的结果。在这项研究中，我们专注于两个四个EP受体，EP 2和EP 4，因为它们是已知的诱导环磷酸腺苷（cAMP）依赖性信号通路。使用原代人气道平滑肌（ASM）细胞，我们首先关注PGE（2）诱导的两种cAMP依赖性促炎介质的产生：白细胞介素6（IL-6）和环氧合酶2的产生。我们发现，PGE（2）诱导的IL-6蛋白分泌通过EP2介导的途径发生，其方式独立于受体介导的对信使RNA（mRNA）表达的影响和转录因子cAMP反应元件结合的时间激活动力学。此外，用PGE（2）刺激ASM没有建立一个正的、受体介导的反馈环，因为EP 2和EP 4受体的mRNA表达没有上调，受体拮抗剂没有作用。我们的研究表明，EP2，而不是EP4，受体负责PGE诱导的（2）-肾上腺素能脱敏（2）。我们证明，PGE（2）诱导的异源受体脱敏负责快速耐受短-（沙丁胺醇）或长-（福莫特罗）（2）-激动剂（测量cAMP释放）可以逆转的EP 2受体拮抗剂PF-04418948。重要的是，这项研究强调了抑制EP2受体在体外恢复（2）-肾上腺素能受体功能，并为未来治疗慢性呼吸道疾病患者的感染性加重提供了一个有吸引力的新治疗靶点。
Prostaglandin E-2 (PGE(2)) is a key prostanoid known to have both proinflammatory and anti-inflammatory impact in the context of chronic respiratory diseases. We hypothesize that these opposing effects may be the result of different prostanoid E (EP) receptor-mediated signaling pathways. In this study, we focus on two of the four EP receptors, EP2 and EP4, as they are known to induce cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. Using primary human airway smooth muscle (ASM) cells, we first focussed on the PGE(2)-induced production of two cAMP-dependent proinflammatory mediators: interleukin 6 (IL-6) and cyclo-oxygenase 2 production. We show that PGE(2)-induced IL-6 protein secretion occurs via an EP2-mediated pathway, in a manner independent of receptor-mediated effects on messenger RNA (mRNA) expression and temporal activation kinetics of the transcription factor cAMP response element binding. Moreover, stimulation of ASM with PGE(2) did not establish a positive, receptor-mediated, feedback loop, as mRNA expression for EP2 and EP4 receptors were not upregulated and receptor antagonists were without effect. Our studies revealed that the EP2, but not the EP4, receptor is responsible for (2)-adrenergic desensitization induced by PGE(2). We demonstrate that PGE(2)-induced heterologous receptor desensitization responsible for tachyphylaxis to short- (salbutamol) or long- (formoterol) (2)-agonists (measured by cAMP release) can be reversed by the EP2 receptor antagonist PF-04418948. Importantly, this study highlights that inhibiting the EP2 receptor restores (2)-adrenergic receptor function in vitro and offers an attractive novel therapeutic target for treating infectious exacerbations in people suffering from chronic respiratory diseases in the future.