Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia.
J Cell Physiol. 2019 Jul;234(7):11070-11077. doi: 10.1002/jcp.27938. Epub 2018 Dec 7.
Prostaglandin E (PGE ) 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, EP and EP , 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 -induced production of two cAMP-dependent proinflammatory mediators: interleukin 6 (IL-6) and cyclo-oxygenase 2 production. We show that PGE -induced IL-6 protein secretion occurs via an EP -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 did not establish a positive, receptor-mediated, feedback loop, as mRNA expression for EP and EP receptors were not upregulated and receptor antagonists were without effect. Our studies revealed that the EP , but not the EP , receptor is responsible for β -adrenergic desensitization induced by PGE . We demonstrate that PGE -induced heterologous receptor desensitization responsible for tachyphylaxis to short- (salbutamol) or long- (formoterol) β -agonists (measured by cAMP release) can be reversed by the EP receptor antagonist PF-04418948. Importantly, this study highlights that inhibiting the EP receptor restores β -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.
前列腺素 E（PGE）是一种已知的关键前列腺素，在慢性呼吸道疾病中具有促炎和抗炎作用。我们假设这些相反的作用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，我们专注于四个 EP 受体中的两个，EP 和 EP，因为它们已知会诱导环腺苷酸单磷酸（cAMP）依赖性信号通路。使用原代人呼吸道平滑肌（ASM）细胞，我们首先专注于 PGE 诱导的两种 cAMP 依赖性促炎介质的产生：白细胞介素 6（IL-6）和环加氧酶 2 的产生。我们表明，PGE 诱导的 IL-6 蛋白分泌是通过 EP 介导的途径发生的，其方式独立于受体介导的信使 RNA（mRNA）表达和转录因子 cAMP 反应元件结合的时空激活动力学的影响。此外，PGE 刺激 ASM 不会建立正向、受体介导的反馈环，因为 EP 和 EP 受体的 mRNA 表达没有上调，受体拮抗剂也没有作用。我们的研究表明，EP 受体，而不是 EP 受体，负责 PGE 诱导的β-肾上腺素能脱敏。我们证明，PGE 诱导的异源受体脱敏负责短效（沙丁胺醇）或长效（福莫特罗）β-激动剂（通过 cAMP 释放测量）的快速耐受，可以通过 EP 受体拮抗剂 PF-04418948 逆转。重要的是，这项研究强调，抑制 EP 受体可恢复β-肾上腺素能受体功能体外，并为将来治疗患有慢性呼吸道疾病的人感染性加重提供了有吸引力的新治疗靶点。
