EP and EP receptor antagonists: Impact on cytokine production and β -adrenergic receptor desensitization in human airway smooth muscle.

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.