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.
Highlights
Asthma is a chronic airway disease characterized by excessive inflammation
Mitogen-activated protein kinase phosphatase 1 (MKP-1) is known to be corticosteroid-responsive [10,20] and increased by cAMP-mediated signalling [20] in airway smooth muscle (ASM) cells, the upregulation of this critical anti-inflammatory protein by long-acting b2-agonists and clinically-used corticosteroids has been incompletely examined to date
As the final aim of the current study was to demonstrate the anti-inflammatory function of MKP-1 on ASM synthetic function by measuring repression of interleukin 6 (IL-6) and interleukin 8 (IL-8) secretion induced by tumour necrosis factor a (TNFa), it was first important to examine the effects of b2-agonists alone on secretion of these cytokines by ASM cells
Summary
Corticosteroids are widely-used to repress inflammation in asthma and control of asthma symptoms can be improved by combination therapy with long-acting b2-agonists [1,2,3]. Mitogen-activated protein kinase phosphatase 1 (MKP-1) is one such anti-inflammatory protein whose upregulation is increasingly recognized as an important molecular mechanism responsible for the improved anti-inflammatory action of corticosteroids and long-acting b2-agonists in combination. The increased expression of MKP-1 may explain the beneficial effects of b2-agonists/corticosteroid combination therapies in the repression of inflammatory gene expression in asthma [12,16]. The upregulation of this critical anti-inflammatory protein by long-acting b2-agonists and clinically-used corticosteroids has been incompletely examined to date
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