title: Matrix metalloproteinase 8 contributes to solubilization of IL-13 receptor alpha2 in vivo.
abstract: BACKGROUND
  IL-13 receptor alpha2 (IL-13R alpha 2) is a high-affinity receptor for IL-13, a central mediator of allergic asthma. It acts predominantly as a decoy receptor but can also contribute to IL-13 responses under certain conditions. IL-13R alpha 2 exists in soluble and membrane forms, which can both bind IL-13 and modulate its activity. Yet the proteolytic processes that contribute to the generation of soluble IL-13R alpha 2 are largely unknown.
  
  
  OBJECTIVE
  We sought to investigate the role of matrix metalloproteinases (MMPs) in the generation of soluble IL-13R alpha 2.
  
  
  METHODS
  Acellular cleavage assays by MMPs were performed by using glutathione-S-transferase fusion proteins of murine or human IL-13R alpha 2. IL-13R alpha 2 stable-transfected cells were used for analysis of surface expression and release of soluble IL-13R alpha 2. Wild-type and MMP-8-deficient mice were used for analysis of allergen-induced airway hyperresponsiveness and solubilization of IL-13R alpha 2.
  
  
  RESULTS
  Among several MMPs tested, only MMP-8 cleaved IL-13R alpha 2. Treatment of transfected human or murine cells expressing high levels of surface IL-13R alpha 2 with MMP-8 resulted in release of soluble IL-13R alpha 2 into the supernatants, with a concomitant decrease in surface IL-13R alpha 2 levels. The IL-13R alpha 2 solubilized by MMP-8 retained IL-13 binding activity. In an asthma model MMP-8-deficient mice displayed increased airway hyperresponsiveness and decreased soluble IL-13R alpha 2 protein levels in bronchoalveolar lavage fluid compared with those seen in wild-type mice after house dust mite challenge.
  
  
  CONCLUSIONS
  MMP-8 cleaves IL-13R alpha 2 in vitro and contributes to the solubilization of IL-13R alpha 2 in vivo.
authors.affiliation: Division of Allergy and Immunology, Institute for Personalized and Predictive Medicine, Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Chen
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tabata
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Gibson
authors.forename: Michael O
authors.initials: MO
authors.lastname: Daines
authors.forename: Manoj R
authors.initials: MR
authors.lastname: Warrier
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
authors.forename: Gurjit K Khurana
authors.initials: GK
authors.lastname: Hershey
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002460:Cell Line; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000097:blood / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000201:enzymology / Q000276:immunology; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D039981:Pyroglyphidae / Q000276:immunology* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D020298:U937 Cells
chemical_list: D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D020784:Matrix Metalloproteinase 8