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Molecular Pharmacology

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Research ArticleArticle

Superiority of Combined Phosphodiesterase PDE3/PDE4 Inhibition over PDE4 Inhibition Alone on Glucocorticoid- and Long-Acting β2-Adrenoceptor Agonist–Induced Gene Expression in Human Airway Epithelial Cells

Hawazen BinMahfouz, Bibhusana Borthakur, Dong Yan, Tresa George, Mark A. Giembycz and Robert Newton
Molecular Pharmacology January 2015, 87 (1) 64-76; DOI: https://doi.org/10.1124/mol.114.093393
Hawazen BinMahfouz
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Bibhusana Borthakur
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Dong Yan
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Tresa George
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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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
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Robert Newton
Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Abstract

Glucocorticoids, also known as corticosteroids, induce effector gene transcription as a part of their anti-inflammatory mechanisms of action. Such genomic effects can be significantly enhanced by long-acting β2-adrenoceptor agonists (LABAs) and may contribute to the clinical superiority of inhaled corticosteroid (ICS)/LABA combinations in asthma and chronic obstructive pulmonary disease (COPD) over ICSs alone. Using models of cAMP- and glucocorticoid-induced transcription in human bronchial epithelial BEAS-2B cells, we show that combining inhibitors of phosphodiesterase (PDE) 3 and PDE4 provides greater benefits compared with inhibiting either PDE alone. In respect to cAMP-dependent transcription, inhibitors of PDE3 (siguazodan, cilostazol) and PDE4 (rolipram, GSK256066, roflumilast N-oxide) each sensitized to the LABA, formoterol. This effect was magnified by dual PDE3 and PDE4 inhibition. Siguazodan plus rolipram was also more effective at inducing cAMP-dependent transcription than either inhibitor alone. Conversely, the concentration-response curve describing the enhancement of dexamethasone-induced, glucocorticoid response element–dependent transcription by formoterol was displaced to the left by PDE4, but not PDE3, inhibition. Overall, similar effects were described for bona fide genes, including RGS2, CD200, and CRISPLD2. Importantly, the combination of siguazodan plus rolipram prolonged the duration of gene expression induced by formoterol, dexamethasone, or dexamethasone plus formoterol. This was most apparent for RGS2, a bronchoprotective gene that may also reduce the proinflammatory effects of constrictor mediators. Collectively, these data provide a rationale for the use of PDE3 and PDE4 inhibitors in the treatment of COPD and asthma where they may enhance, sensitize, and prolong the effects of LABA/ICS combination therapies.

Footnotes

    • Received April 20, 2014.
    • Accepted October 16, 2014.
  • This research was supported by the Canadian Institutes of Health Research [Operating Grants (to R.N. and M.A.G.)], the Lung Association of Alberta and Northwest Territories [Studentship Awards (to T.G.)], and Alberta Innovates-Health Solutions (AI-HS) [(to D.Y.)]. R.N. is an AI-HS Senior Scholar. M.A.G. holds a Tier 1 Canada Research Chair in Pulmonary Pharmacology. H.B. received a scholarship from the Ministry of Higher Education in Saudi Arabia. A grant from the Canadian Fund for Innovation and the Alberta Science and Research Authority provided equipment and infrastructure for conducting real-time polymerase chain reaction.

  • dx.doi.org/10.1124/mol.114.093393.

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

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (1)
Molecular Pharmacology
Vol. 87, Issue 1
1 Jan 2015
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Research ArticleArticle

PDE3/PDE4 Inhibition on CRE- and GRE-Dependent Transcription

Hawazen BinMahfouz, Bibhusana Borthakur, Dong Yan, Tresa George, Mark A. Giembycz and Robert Newton
Molecular Pharmacology January 1, 2015, 87 (1) 64-76; DOI: https://doi.org/10.1124/mol.114.093393

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Research ArticleArticle

PDE3/PDE4 Inhibition on CRE- and GRE-Dependent Transcription

Hawazen BinMahfouz, Bibhusana Borthakur, Dong Yan, Tresa George, Mark A. Giembycz and Robert Newton
Molecular Pharmacology January 1, 2015, 87 (1) 64-76; DOI: https://doi.org/10.1124/mol.114.093393
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