Corticosteroids and β2‐agonists upregulate mitogen‐activated protein kinase phosphatase 1: in vitro mechanisms

BACKGROUND AND PURPOSEAirway 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 APPROACHHerein 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 RESULTSMKP‐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 IMPLICATIONSTaken 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.