title: Long-acting β2-agonists increase fluticasone propionate-induced mitogen-activated protein kinase phosphatase 1 (MKP-1) in airway smooth muscle cells.
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.
authors.affiliation: Respiratory Research Group, Faculty of Pharmacy, University of Sydney, Sydney, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Manetsch
authors.forename: Md Mostafizur
authors.initials: MM
authors.lastname: Rahman
authors.forename: Brijeshkumar S
authors.initials: BS
authors.lastname: Patel
authors.forename: Emma E
authors.initials: EE
authors.lastname: Ramsay
authors.forename: Nowshin N
authors.initials: NN
authors.lastname: Rumzhum
authors.forename: Hatem
authors.initials: H
authors.lastname: Alkhouri
authors.forename: Qi
authors.initials: Q
authors.lastname: Ge
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000068298:Fluticasone; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000730:Androstadienes; D000068298:Fluticasone; D054638:Dual Specificity Phosphatase 1