Abstract
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.
Footnotes
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The current study was funded in part by a research award from AstraZeneca and a National Heart and Lung Institute Foundation Studentship. R.N. is a Canadian Institutes of Health Research (CIHR) New Investigator and Alberta Heritage Foundation for Medical Research (AHFMR) Scholar. M.A.G. is an AHFMR Senior Scholar. Work in the laboratories of R.N. and M.A.G. is also supported by CIHR, AHFMR, and research awards from Altana and Glaxo-SmithKline.
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ABBREVIATIONS: ICS, inhaled corticosteroid; GR, glucocorticoid receptor; LABA, long-acting β2-adrenoceptor agonist; PKA, cAMP-dependent protein kinas; GRE, glucocorticoid response element; HASM, human airway smooth muscle; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; SFM, serum-free medium; ICI 118,551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride; PG, prostaglandin; 8-Br-cAMP, 8-bromo-cAMP; MOI, multiplicity of infection; PCR, polymerase chain reaction; ICI 118,551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride; PKI, protein kinase inhibitor; GILZ, glucocorticoid-inducible leucine zipper; TTP, tristetraprolin; MT1X, metallothionein 1X; MKP, mitogen-activated protein kinase phosphatase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; FKBP51, FK508 binding protein 51.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received July 16, 2007.
- Accepted September 26, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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