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

Br J Pharmacol. 2012 Aug;166(7):2049-59. doi: 10.1111/j.1476-5381.2012.01923.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / pharmacology*
  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Dexamethasone / pharmacology*
  • Dual Specificity Phosphatase 1 / biosynthesis*
  • Dual Specificity Phosphatase 1 / genetics
  • Ethanolamines / pharmacology*
  • Formoterol Fumarate
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • RNA, Messenger / biosynthesis
  • Tumor Cells, Cultured
  • Up-Regulation


  • Adrenal Cortex Hormones
  • Adrenergic beta-2 Receptor Agonists
  • Ethanolamines
  • RNA, Messenger
  • Dexamethasone
  • Dual Specificity Phosphatase 1
  • Formoterol Fumarate