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

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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Manetsch M,Ramsay EE,King EM,Seidel P,Che W,Ge Q,Hibbs DE,Newton R,Ammit AJ

doi

10.1111/j.1476-5381.2012.01923.x

subject

Has Abstract

pub_date

2012-08-01 00:00:00

pages

2049-59

issue

eissn

0007-1188

issn

1476-5381

journal_volume

166

pub_type

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