Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/98105
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Type: | Journal article |
Title: | Long-acting β2-agonists increase fluticasone propionate-induced mitogen-activated protein kinase phosphatase 1 (MKP-1) in airway smooth muscle cells |
Other Titles: | Long-acting beta2-agonists increase fluticasone propionate-induced mitogen-activated protein kinase phosphatase 1 (MKP-1) in airway smooth muscle cells |
Author: | Manetsch, M. Rahman, M. Patel, B. Ramsay, E. Rumzhum, N. Alkhouri, H. Ge, Q. Ammit, A. |
Citation: | PLoS One, 2013; 8(3):e59635-1-e59635-9 |
Publisher: | Public Library of Science |
Issue Date: | 2013 |
ISSN: | 1932-6203 1932-6203 |
Editor: | Ito, K. |
Statement of Responsibility: | Melanie Manetsch, Md. Mostafizur Rahman, Brijeshkumar S. Patel, Emma E. Ramsay, Nowshin N. Rumzhum, Hatem Alkhouri, Qi Ge, Alaina J. Ammit |
Abstract: | Mitogen-activated protein kinase phosphatase 1 (MKP-1) represses MAPK-driven signalling and plays an important anti-inflammatory role in asthma and airway remodelling. Although MKP-1 is corticosteroid-responsive and increased by cAMP-mediated signalling, the upregulation of this critical anti-inflammatory protein by long-acting β2-agonists and clinically-used corticosteroids has been incompletely examined to date. To address this, we investigated MKP-1 gene expression and protein upregulation induced by two long-acting β2-agonists (salmeterol and formoterol), alone or in combination with the corticosteroid fluticasone propionate (abbreviated as fluticasone) in primary human airway smooth muscle (ASM) cells in vitro. β2-agonists increased MKP-1 protein in a rapid but transient manner, while fluticasone induced sustained upregulation. Together, long-acting β2-agonists increased fluticasone-induced MKP-1 and modulated ASM synthetic function (measured by interleukin 6 (IL-6) and interleukin 8 (IL-8) secretion). As IL-6 expression (like MKP-1) is cAMP/adenylate cyclase-mediated, the long-acting β2-agonist formoterol increased IL-6 mRNA expression and secretion. Nevertheless, when added in combination with fluticasone, β2-agonists significantly repressed IL-6 secretion induced by tumour necrosis factor α (TNFα). Conversely, as IL-8 is not cAMP-responsive, β2-agonists significantly inhibited TNFα-induced IL-8 in combination with fluticasone, where fluticasone alone was without repressive effect. In summary, long-acting β2-agonists increase fluticasone-induced MKP-1 in ASM cells and repress synthetic function of this immunomodulatory airway cell type. |
Keywords: | Cells, Cultured Myocytes, Smooth Muscle Humans Androstadienes Blotting, Western Enzyme-Linked Immunosorbent Assay Dual Specificity Phosphatase 1 Adrenergic beta-2 Receptor Agonists Real-Time Polymerase Chain Reaction Fluticasone |
Rights: | © 2013 Manetsch et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
DOI: | 10.1371/journal.pone.0059635 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/570856 |
Published version: | http://dx.doi.org/10.1371/journal.pone.0059635 |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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hdl_98105.pdf | Published version | 1.71 MB | Adobe PDF | View/Open |
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