title: Corticosteroids and β₂-agonists upregulate mitogen-activated protein kinase phosphatase 1: in vitro mechanisms.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Respiratory Research Group, Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Manetsch
authors.forename: E E
authors.initials: EE
authors.lastname: Ramsay
authors.forename: E M
authors.initials: EM
authors.lastname: King
authors.forename: P
authors.initials: P
authors.lastname: Seidel
authors.forename: W
authors.initials: W
authors.lastname: Che
authors.forename: Q
authors.initials: Q
authors.lastname: Ge
authors.forename: D E
authors.initials: DE
authors.lastname: Hibbs
authors.forename: R
authors.initials: R
authors.lastname: Newton
authors.forename: A J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis* / Q000235:genetics; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D012333:RNA, Messenger / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D004983:Ethanolamines; D012333:RNA, Messenger; D003907:Dexamethasone; D054638:Dual Specificity Phosphatase 1; D000068759:Formoterol Fumarate