Abstract
BACKGROUND AND PURPOSE Airway remodelling is a consequence of long-term inflammation and MAPKs are key signalling molecules that drive pro-inflammatory pathways. The endogenous MAPK deactivator - MAPK phosphatase 1 (MKP-1) - is a critical negative regulator of the myriad pro-inflammatory pathways activated by MAPKs in the airway. EXPERIMENTAL APPROACH Herein we investigated the molecular mechanisms responsible for the upregulation of MKP-1 in airway smooth muscle (ASM) by the corticosteroid dexamethasone and the β2-agonist formoterol, added alone and in combination. KEY RESULTS MKP-1 is a corticosteroid-inducible gene whose expression is enhanced by long-acting β2-agonists in an additive manner. Formoterol induced MKP-1 expression via the β2-adrenoceptor and we provide the first direct evidence (utilizing overexpression of PKIα, a highly selective PKA inhibitor) to show that PKA mediates β2-agonist-induced MKP-1 upregulation. Dexamethasone activated MKP-1 transcription in ASM cells via a cis-acting corticosteroid-responsive region located between -1380 and -1266 bp of the MKP-1 promoter. While the 3'-untranslated region of MKP-1 contains adenylate + uridylate elements responsible for regulation at the post-transcriptional level, actinomycin D chase experiments revealed that there was no increase in MKP-1 mRNA stability in the presence of dexamethasone, formoterol, alone or in combination. Rather, there was an additive effect of the asthma therapeutics on MKP-1 transcription. CONCLUSIONS AND IMPLICATIONS Taken together, these studies allow us a greater understanding of the molecular basis of MKP-1 regulation by corticosteroids and β2-agonists and this new knowledge may lead to elucidation of optimized corticosteroid-sparing therapies in the future.
Original language | English (US) |
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Pages (from-to) | 2049-2059 |
Number of pages | 11 |
Journal | British Journal of Pharmacology |
Volume | 166 |
Issue number | 7 |
DOIs | |
State | Published - Aug 2012 |
Keywords
- PKA
- PKIα
- airway smooth muscle
- corticosteroids
- glucocorticoid-response elements
- β-agonists
ASJC Scopus subject areas
- Pharmacology