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Research ArticleInflammation, Immunopharmacology, and Asthma

Induction of Regulator of G-Protein Signaling 2 Expression by Long-Acting β2-Adrenoceptor Agonists and Glucocorticoids in Human Airway Epithelial Cells

Neil S. Holden, Tresa George, Christopher F. Rider, Ambika Chandrasekhar, Suharsh Shah, Manminder Kaur, Malcolm Johnson, David P. Siderovski, Richard Leigh, Mark A. Giembycz and Robert Newton
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 12-24; DOI: https://doi.org/10.1124/jpet.113.204586
Neil S. Holden
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Tresa George
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Christopher F. Rider
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Ambika Chandrasekhar
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Suharsh Shah
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Manminder Kaur
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Malcolm Johnson
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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David P. Siderovski
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Richard Leigh
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Mark A. Giembycz
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Robert Newton
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (N.S.H., T.G., C.F.R., A.C., S.S., M.K., R.L., M.A.G., R.N.); GlaxoSmithKline Research and Development, Uxbridge, Middlesex, United Kingdom (M.J.); and Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia (D.P.S.)
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Abstract

In asthma and chronic obstructive pulmonary disease (COPD) multiple mediators act on Gαq-linked G-protein-coupled receptors (GPCRs) to cause bronchoconstriction. However, acting on the airway epithelium, such mediators may also elicit inflammatory responses. In human bronchial epithelial BEAS-2B cells (bronchial epithelium + adenovirus 12-SV40 hybrid), regulator of G-protein signaling (RGS) 2 mRNA and protein were synergistically induced in response to combinations of long-acting β2-adrenoceptor agonist (LABA) (salmeterol, formoterol) plus glucocorticoid (dexamethasone, fluticasone propionate, budesonide). Equivalent responses occurred in primary human bronchial epithelial cells. Concentrations of glucocorticoid plus LABA required to induce RGS2 expression in BEAS-2B cells were consistent with the levels achieved therapeutically in the lungs. As RGS2 is a GTPase-activating protein that switches off Gαq, intracellular free calcium ([Ca2+]i) flux was used as a surrogate of responses induced by histamine, methacholine, and the thromboxane receptor agonist U46619 [(Z)-7-[(1S,4R,5R,6S)-5-[(E,3S)-3-hydroxyoct-1-enyl]-3-oxabicyclo[2.2.1]heptan-6-yl]hept-5-enoic acid]. This was significantly attenuated by salmeterol plus dexamethasone pretreatment, or RGS2 overexpression, and the protective effect of salmeterol plus dexamethasone was abolished by RGS2 RNA silencing. Although methacholine and U46619 induced interleukin-8 (IL-8) release and this was inhibited by RGS2 overexpression, the repression of U46619-induced IL-8 release by salmeterol plus dexamethasone was unaffected by RGS2 knockdown. Given a role for Gαq-mediated pathways in inducing IL-8 release, we propose that RGS2 acts redundantly with other effector processes to repress IL-8 expression. Thus, RGS2 expression is a novel effector mechanism in the airway epithelium that is induced by glucocorticoid/LABA combinations. This could contribute to the efficacy of glucocorticoid/LABA combinations in asthma and COPD.

Footnotes

    • Received March 6, 2013.
    • Accepted October 25, 2013.
  • ↵1 Current affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden.

  • ↵2 Current affiliation: University of Manchester, NIHR Translational Research Facility, University Hospital of South Manchester, United Kingdom.

  • This research was supported by grants from the GlaxoSmithKline Collaborative Innovative Research Fund, GlaxoSmithKline Canada (to R.N., M.A.G., R.L.); operating grants from the Canadian Institutes of Health Research (R.N.); studentship support from GlaxoSmithKline, UK (to R.N., M.A.G.), studentship awards from the Lung Association of Alberta and NWT (to T.G., C.F.R., S.S.) and from Alberta Innovates-Health Solutions (AI-HS) (C.F.R.); an Izaak Walton Killam Post-doctoral Fellowship (to N.S.H.). R.N. and R.L. are AI-HS Senior Scholars and Clinical Investigators respectively. M.A.G. holds a Tier 1 Canada Research Chair in Pulmonary Pharmacology. A grant from the Canadian Fund for Innovation (CFI) and the Alberta Science and Research Authority provided equipment and infrastructure for conducting real-time polymerase chain reaction.

  • dx.doi.org/10.1124/jpet.113.204586.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 1
1 Jan 2014
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Research ArticleInflammation, Immunopharmacology, and Asthma

RGS2 Expression in Bronchial Epithelial Cells

Neil S. Holden, Tresa George, Christopher F. Rider, Ambika Chandrasekhar, Suharsh Shah, Manminder Kaur, Malcolm Johnson, David P. Siderovski, Richard Leigh, Mark A. Giembycz and Robert Newton
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 12-24; DOI: https://doi.org/10.1124/jpet.113.204586

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Research ArticleInflammation, Immunopharmacology, and Asthma

RGS2 Expression in Bronchial Epithelial Cells

Neil S. Holden, Tresa George, Christopher F. Rider, Ambika Chandrasekhar, Suharsh Shah, Manminder Kaur, Malcolm Johnson, David P. Siderovski, Richard Leigh, Mark A. Giembycz and Robert Newton
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 12-24; DOI: https://doi.org/10.1124/jpet.113.204586
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