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Long-Acting β₂-Adrenoceptor Agonists Synergistically Enhance Glucocorticoid-Dependent Transcription in Human Airway Epithelial and Smooth Muscle Cells

Airway Inflammation Group, Departments of Cell Biology and Anatomy, and Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

Addition of an inhaled long-acting β₂-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 β₂-adrenoceptor agonist-induced 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 β₂-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, β₂-adrenoceptor agonists synergistically enhance simple GRE-dependent transcription via the classical cAMP-PKA pathway. Consistent with the clinical situation, the addition of a β₂-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 β₂-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/β₂-adrenoceptor agonist combinations in a manner that was consistent with the GRE-reporter. 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.

Address correspondence to: Dr. Robert Newton, Department of Cell Biology and Anatomy, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4N1, Canada, E-mail: rnewton{at}ucalgary.ca

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				M. Kaur, N. S. Holden, S. M. Wilson, M. B. Sukkar, K. F. Chung, P. J. Barnes, R. Newton, and M. A. Giembycz Effect of {beta}2-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A Am J Physiol Lung Cell Mol Physiol, September 1, 2008; 295(3): L505 - L514. [Abstract] [Full Text] [PDF]