EP <inf>2</inf> and EP <inf>4</inf> receptor antagonists: Impact on cytokine production and β <inf>2</inf> -adrenergic receptor desensitization in human airway smooth muscle

© 2018 Wiley Periodicals, Inc. 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, EP 2 and EP 4 , 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 EP 2 -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 EP 2 and EP 4 receptors were not upregulated and receptor antagonists were without effect. Our studies revealed that the EP 2 , but not the EP 4 , receptor is responsible for β 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) β 2 -agonists (measured by cAMP release) can be reversed by the EP 2 receptor antagonist PF-04418948. Importantly, this study highlights that inhibiting the EP 2 receptor restores β 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