Enhancement of inflammatory mediator release by β₂‐adrenoceptor agonists in airway epithelial cells is reversed by glucocorticoid action

Background and purpose:  Due to their potent bronchodilator properties, β₂‐adrenoceptor agonists are a mainstay of therapy in asthma. However, the effects of β₂‐adrenoceptor agonists on inflammation are less clear. Accordingly, we have investigated the effects of β₂‐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 β₂‐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 (PGE₂, forskolin). Enhancement of cytokine release by β₂‐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 β₂‐adrenoceptor agonists in asthma. As increased inflammatory mediator expression is prevented by the addition of glucocorticoid to the β₂‐adrenoceptor, our data provide further mechanistic support for the use of combination therapies in asthma management.

DOI: 10.1111/j.1476-5381.2010.00708.x

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