title: Downregulation of a disintegrin and metalloproteinase 33 by IFN-gamma in human airway smooth muscle cells.
abstract: BACKGROUND
  A disintegrin and metalloproteinase 33 (ADAM33) has been identified as a susceptibility gene for asthma. ADAM33 is expressed in airway smooth muscle (ASM) cells and is suggested to play a role in the function of these cells. However, there is little information on the regulation of ADAM33.
  
  
  OBJECTIVE
  To investigate whether ADAM33 is more highly expressed in ASM cells of patients with asthma than in those of normal subjects, and whether there is any inflammatory mediator (asthma-related cytokine/chemokine) that could modulate the expression of ADAM33 in ASM cells.
  
  
  METHODS
  smRNA and protein expression of ADAM33 in bronchial biopsy specimens was investigated (in situ hybridization and immunohistochemistry). Effects of cytokines on expression of ADAM33 in cultured human ASM cells were evaluated by measuring mRNA (real-time RT-PCR) and protein (Western blotting).
  
  
  RESULTS
  ADAM33 mRNA and protein in biopsied specimens were more highly expressed in ASM cells of patients with asthma than in cells of normal subjects. Cultured ASM cells expressed ADAM33 at both the mRNA and the protein levels. IFN-gamma reduced the mRNA expression dose-dependently and time-dependently, whereas IL-4 and IL-13 or chemokines did not affect the expression. The reduction by IFN-gamma was partially restored by U0126, inhibitor for mitogen-activated protein kinase kinase 1/2, suggesting a role for extracellular signal-regulated kinase pathway. Further studies using cycloheximide and actinomycin-D suggested that the downregulation was at the transcriptional level.
  
  
  CONCLUSIONS
  The expression of ADAM33 by ASM cells is increased in patients with asthma, and its expression may be regulated by IFN-gamma.
  
  
  CONCLUSIONS
  IFN-gamma might have a role in suppressing ADAM33 in ASM cells.
authors.affiliation: Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada, H2X 2P2.
authors.forename: Isao
authors.initials: I
authors.lastname: Ito
authors.forename: Johanne D
authors.initials: JD
authors.lastname: Laporte
authors.forename: Pierre O
authors.initials: PO
authors.lastname: Fiset
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Asai
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamauchi
authors.forename: James G
authors.initials: JG
authors.lastname: Martin
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D001249:Asthma / Q000378:metabolism*; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D018793:Interleukin-13; D020033:Protein Isoforms; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; C450441:ADAM33 protein, human