Cytokines Regulate β-2-Adrenergic Receptor Responsiveness in Airway Smooth Muscle via Multiple PKA- and EP2 Receptor-Dependent Mechanisms

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Abstract
β2AR desensitization in airway smooth muscle (ASM) mediated by airway inflammation has been proposed to contribute to asthma pathogenesis and diminished efficacy of β-agonist therapy. Mechanistic insight into this phenomenon is largely conceptual and lacks direct empirical evidence. Here, we employ molecular and genetic strategies to reveal mechanisms mediating cytokine effects on ASM β2AR responsiveness. Ectopic expression of inhibitory peptide (PKI-GFP) or a mutant regulatory subunit of PKA (RevAB-GFP) effectively inhibited intracellular PKA activity in cultured human ASM cells and enhanced β2AR responsiveness by mitigating both agonist-specific (β-agonist-mediated) desensitization and cytokine (IL-1β and TNF-α)-induced heterologous desensitization via actions on multiple targets. In the absence of cytokine treatment, PKA inhibition increased β2AR-mediated signaling by increasing both β2AR−G protein coupling and intrinsic adenylyl cyclase activity. PKI-GFP and RevAB-GFP expression also conferred resistance to cytokine-promoted β2AR−G protein uncoupling and disrupted feed-forward mechanisms of PKA activation by attenuating the induction of COX-2 and PGE2. Cytokine treatment of tracheal ring preparations from wild-type mice resulted in a profound loss of β-agonist-mediated relaxation of methacholine-contracted rings, whereas rings from EP2 receptor knockout mice were largely resistant to cytokine-mediated β2AR desensitization. These findings identify EP2 receptor- and PKA-dependent mechanisms as the principal effectors of cytokine-mediated β2AR desensitization in ASM.

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