Received for publication July 17, 2007.
Revised September 26, 2007.
Accepted for publication September 26, 2007.

Long-acting ₂-adrenoceptor agonists synergistically enhance glucocorticoid-dependent transcription in human airways epithelial and smooth muscle cells

Abstract

Addition of an inhaled long-acting 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. Since 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 ₂-adrenoceptor agonist-induced cAMP-response element (CRE)-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 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, ₂-adrenoceptor agonists synergistically enhance simple GRE-dependent transcription via the classical cAMP-PKA pathway. Consistent with the clinical situation, the addition of a ₂-adrenoceptor agonist to a glucocorticoid is steroid sparing in that maximal GRE-dependent responses, evoked by glucocorticoid, are achieved at ~10-fold lower concentrations in the presence of ₂-adrenoceptor agonist. Finally, analysis of dexamethasone-inducible genes including, GILZ, aminopeptidase N, FKBP51, PAI-1, tristetraprolin, DNB5, p57KIP2, metallothionein 1X and MKP-1, revealed enhanced inducibility of some genes by glucocorticoid/₂-adrenoceptor agonist combinations in a manner that was consistent with the GRE-reporter. Since such effects also occur in primary human airways 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.

Key words: Adrenergic, Glucorticoids/Mineralocorticoids, cAMP, Protein Kinase A

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