Matrix metalloproteinase 8 contributes to solubilization of IL-13 receptor alpha2 in vivo

J Allergy Clin Immunol. 2008 Sep;122(3):625-32. doi: 10.1016/j.jaci.2008.06.022. Epub 2008 Aug 9.

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.

Conclusion: MMP-8 cleaves IL-13R alpha 2 in vitro and contributes to the solubilization of IL-13R alpha 2 in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Asthma / immunology*
  • Asthma / metabolism
  • Bronchoalveolar Lavage Fluid / immunology
  • Cell Line
  • Humans
  • Interleukin-13 / immunology
  • Interleukin-13 / metabolism
  • Interleukin-13 Receptor alpha2 Subunit / blood
  • Interleukin-13 Receptor alpha2 Subunit / chemistry
  • Interleukin-13 Receptor alpha2 Subunit / immunology
  • Interleukin-13 Receptor alpha2 Subunit / metabolism*
  • Lung / enzymology
  • Lung / immunology
  • Matrix Metalloproteinase 8 / deficiency
  • Matrix Metalloproteinase 8 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Pyroglyphidae / immunology*
  • Pyroglyphidae / metabolism
  • Respiratory Hypersensitivity / immunology*
  • Respiratory Hypersensitivity / metabolism
  • U937 Cells

Substances

  • Interleukin-13
  • Interleukin-13 Receptor alpha2 Subunit
  • Matrix Metalloproteinase 8