Please use this identifier to cite or link to this item: http://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
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.
RMID: 0030044938
DOI: 10.1371/journal.pone.0059635
Grant ID: http://purl.org/au-research/grants/nhmrc/570856
Appears in Collections:Medicine publications

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