title: IL-13 and TH2 cytokine exposure triggers matrix metalloproteinase 7-mediated Fas ligand cleavage from bronchial epithelial cells.
abstract: BACKGROUND
  Bronchial epithelial damage and activation likely contribute to the inflammatory and airway-remodeling events characteristic of severe asthma. Interaction of Fas receptor (CD95) with its ligand (FasL; CD95L) is an important mechanism of cell-mediated apoptosis. Bronchial epithelial FasL expression provides immune barrier protection from immune cell-mediated damage.
  
  
  OBJECTIVE
  Membrane FasL (mFasL) is a cleavage target of matrix metalloproteinases (MMPs). We investigated whether the asthmatic T(H)2 environment might influence disease processes by increasing airway epithelial MMP-mediated cleavage of mFasL into proinflammatory soluble FasL.
  
  
  METHODS
  We used human airway epithelial cell lines and primary cells to model the human airway epithelium in vitro. Airway tissue from healthy subjects and patients with severe asthma was used to investigate MMP expression patterns in diseased airways.
  
  
  RESULTS
  We demonstrate that active MMP-7 is present in the ciliated epithelial cells of normal human airways. In patients with severe asthma, MMP-7 levels are increased in basal epithelial cells. Airway epithelial cell lines (1HAEo(-) and 16HBE14o(-)) in vitro express constitutively high levels of MMP-2 and MMP-9 but relatively low levels of MMP-7. T(H)2 cytokine (IL-4, IL-9, and IL-13) treatment of 1HAEo(-) cells increased MMP-7 mRNA and activity, triggered colocalization of intracellular MMP-7 with FasL, and caused mFasL cleavage with soluble FasL release. Small interfering RNA knockdown shows that cytokine-induced mFasL cleavage is dependent on MMP-7 activity.
  
  
  CONCLUSIONS
  MMPs serve multiple beneficial roles in the lung. However, chronic disordered epithelial expression of MMP-7 in patients with asthma might increase mFasL cleavage and contribute to airway epithelial damage and inflammation.
authors.affiliation: UBC James Hogg Research Laboratories, Providence Heart and Lung Institute, University of British Columbia, Vancouver, British Columbia, Canada. samuel.wadsworth@hli.ubc.ca
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Wadsworth
authors.forename: Ryo
authors.initials: R
authors.lastname: Atsuta
authors.forename: J Oliver
authors.initials: JO
authors.lastname: McIntyre
authors.forename: Tillie-Louise
authors.initials: TL
authors.lastname: Hackett
authors.forename: Gurpreet K
authors.initials: GK
authors.lastname: Singhera
authors.forename: Delbert R
authors.initials: DR
authors.lastname: Dorscheid
mesh_terms: D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016906:Interleukin-9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C491901:FAS protein, human; D053222:Fas Ligand Protein; C508598:IL4 protein, human; C508607:IL9 protein, human; D018793:Interleukin-13; D016906:Interleukin-9; D034741:RNA, Small Interfering; D019014:fas Receptor; D015847:Interleukin-4; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9