Long-acting β2-adrenoceptor agonists synergistically enhance glucocorticoid-dependent transcription in human airway epithelial and smooth muscle cells

Addition of an inhaled long-acting beta(2)-adrenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) is more effective at improving asthma control and reducing exacerbations than increasing the dose of ICS. Given that LABA monotherapy is not anti-inflammatory, pathways may exist by which LABAs enhance ICS actions. In the current study, the glucocorticoid dexamethasone had no effect on beta(2)-adrenoceptor agonistinduced cAMP-response element-dependent transcription in the human bronchial epithelial cell line BEAS-2B. In contrast, simple glucocorticoid response element (GRE)-dependent transcription induced by dexamethasone, budesonide, and fluticasone was synergistically enhanced by beta(2)-adrenoceptor agonists, including salmeterol and formoterol, to a level that could not be achieved by glucocorticoid alone. This enhancement was mimicked by other cAMP-elevating agents, and a cAMP mimetic, and was blocked by an inhibitor of cAMP-dependent protein kinase (PKA). Thus, beta(2)-adrenoceptor agonists synergistically enhance simple GRE-dependent transcription via the classical cAMP-PKA pathway. Consistent with the clinical situation, the addition of a beta(2)-adrenoceptor agonist to a glucocorticoid is steroid-sparing in that maximal GRE-dependent responses, evoked by glucocorticoid, are achieved at similar to 10-fold lower concentrations in the presence of beta(2)-adrenoceptor agonist. Finally, analysis of dexamethasone-inducible genes, including glucocorticoid-inducible leucine zipper (GILZ), aminopeptidase N, FKBP51, PAI-1, tristetraprolin, DNB5, p57KIP2, metallothionein 1X, and MKP-1, revealed enhanced inducibility of some genes by glucocorticoid/beta(2)-adrenoceptor agonist combinations in a manner that was consistent with the GREreporter. Because such effects also occur in primary human airway smooth muscle cells, we propose that enhancement of glucocorticoid-inducible gene expression may contribute to the superior efficacy of LABA/ICS combination therapies, over ICS alone, in asthma treatment.