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Research ArticleInflammation, Immunopharmacology, and Asthma

Concurrent Agonism of Adenosine A2B and Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

Stephanie Greer, Cara W. Page, Taruna Joshi, Dong Yan, Robert Newton and Mark A. Giembycz
Journal of Pharmacology and Experimental Therapeutics September 2013, 346 (3) 473-485; DOI: https://doi.org/10.1124/jpet.113.206284
Stephanie Greer
Airways Inflammation Research Group, Departments of Physiology and Pharmacology (S.G., C.W.P., T.J., D.Y., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Cara W. Page
Airways Inflammation Research Group, Departments of Physiology and Pharmacology (S.G., C.W.P., T.J., D.Y., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Taruna Joshi
Airways Inflammation Research Group, Departments of Physiology and Pharmacology (S.G., C.W.P., T.J., D.Y., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Dong Yan
Airways Inflammation Research Group, Departments of Physiology and Pharmacology (S.G., C.W.P., T.J., D.Y., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Robert Newton
Airways Inflammation Research Group, Departments of Physiology and Pharmacology (S.G., C.W.P., T.J., D.Y., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Mark A. Giembycz
Airways Inflammation Research Group, Departments of Physiology and Pharmacology (S.G., C.W.P., T.J., D.Y., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Abstract

Chronic obstructive pulmonary disease (COPD) is a neutrophilic inflammatory disorder that is weakly responsive to glucocorticoids. Identification of ways to enhance the anti-inflammatory activity of glucocorticoids is, therefore, a major research objective. Adenosine receptor agonists that target the A2B-receptor subtype are efficacious in several cell-based assays and preclinical models of inflammation. Accordingly, the present study was designed to determine if a selective A2B-receptor agonist, 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulphanyl]acetamide (Bay 60-6583), and a glucocorticoid, dexamethasone, in combination display putative anti-inflammatory activity that is superior to either drug alone. In BEAS-2B human airway epithelial cells stably transfected with cAMP-response element (CRE) and glucocorticoid response element (GRE) reporter constructs, Bay 60-6583 promoted CRE-dependent transcription and enhanced GRE-dependent transcription by an adenosine A2B-receptor–mediated mechanism that was associated with cAMP formation and abolished by an inhibitor of cAMP-dependent protein kinase. Analysis of the concentration-response relationship that described the enhancement of GRE-dependent transcription showed that Bay 60-6583 increased the magnitude of response without affecting the potency of dexamethasone. Bay 60-6583 and dexamethasone also induced a panel of genes that, collectively, could have benefit in COPD. These were categorized into genes that were induced in a positive cooperative manner (RGS2, p57kip2), an additive manner (TTP, BRL-1), or by Bay 60-6583 (CD200, CRISPLD2, SOCS3) or dexamethasone (GILZ) only. Thus, the gene induction “fingerprints” produced by Bay 60-6583 and dexamethasone, alone and in combination, were distinct. Collectively, through their actions on gene expression, an adenosine A2B-receptor agonist and a glucocorticoid administered together may have utility in the treatment of inflammatory disorders that respond suboptimally to glucocorticoids as a monotherapy.

Footnotes

    • Received May 6, 2013.
    • Accepted July 1, 2013.
  • S.G. and C.W.P. contributed equally to this work.

  • This work was supported by the Canadian Institutes for Health Research [CIHR; MOP 93742]; and the Lung Association, Alberta and North West Territories. The authors declare no conflict of interest.

  • dx.doi.org/10.1124/jpet.113.206284.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 346 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 3
1 Sep 2013
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Research ArticleInflammation, Immunopharmacology, and Asthma

A Novel Combination Therapy for COPD

Stephanie Greer, Cara W. Page, Taruna Joshi, Dong Yan, Robert Newton and Mark A. Giembycz
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 473-485; DOI: https://doi.org/10.1124/jpet.113.206284

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Research ArticleInflammation, Immunopharmacology, and Asthma

A Novel Combination Therapy for COPD

Stephanie Greer, Cara W. Page, Taruna Joshi, Dong Yan, Robert Newton and Mark A. Giembycz
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 473-485; DOI: https://doi.org/10.1124/jpet.113.206284
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