Enhancement of inflammatory mediator release by β 2- adrenoceptor agonists in airway epithelial cells is reversed by glucocorticoid action

Background and purpose: Due to their potent bronchodilator properties, β 2-adrenoceptor agonists are a mainstay of therapy in asthma. However, the effects of β 2-adrenoceptor agonists on inflammation are less clear. Accordingly, we have investigated the effects of β 2-adrenoceptor agonists on inflammatory mediator release. Experimental approach: Transcription factor activation, and both release and mRNA expression of IL-6 and IL-8 were examined by luciferase reporter assay, elisa and real-time RT-PCR in bronchial human epithelial BEAS-2B cells or primary human bronchial epithelial cells grown at an air-liquid interface. Key results: Pre-incubation with β 2-adrenoceptor agonists (salbutamol, salmeterol, formoterol) augmented the release and mRNA expression of IL-6 and IL-8 induced by IL-1β and IL-1β plus histamine, whereas NF-κB-dependent transcription was significantly repressed, and AP-1-dependent transcription was unaffected. These effects were mimicked by other cAMP-elevating agents (PGE 2, forskolin). Enhancement of cytokine release by β 2-adrenoceptor agonists also occurred in primary bronchial epithelial cells. Addition of dexamethasone with salmeterol repressed IL-6 and IL-8 release to levels that were similar to the repression achieved in the absence of salmeterol. IL-6 release was enhanced when salmeterol was added before, concurrently or after IL-1β plus histamine stimulation, whereas IL-8 release was only enhanced by salmeterol addition prior to stimulation. Conclusions and implications: Enhancement of IL-6 and IL-8 release may contribute to the deleterious effects of β 2-adrenoceptor agonists in asthma. As increased inflammatory mediator expression is prevented by the addition of glucocorticoid to the β 2-adrenoceptor, our data provide further mechanistic support for the use of combination therapies in asthma management. © 2010 The British Pharmacological Society.