Mechanisms of allergy and clinical immunology
Matrix metalloproteinase 8 contributes to solubilization of IL-13 receptor α2 in vivo

https://doi.org/10.1016/j.jaci.2008.06.022Get rights and content

Background

IL-13 receptor α2 (IL-13Rα2) 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-13Rα2 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-13Rα2 are largely unknown.

Objective

We sought to investigate the role of matrix metalloproteinases (MMPs) in the generation of soluble IL-13Rα2.

Methods

Acellular cleavage assays by MMPs were performed by using glutathione-S-transferase fusion proteins of murine or human IL-13Rα2. IL-13Rα2 stable-transfected cells were used for analysis of surface expression and release of soluble IL-13Rα2. Wild-type and MMP-8–deficient mice were used for analysis of allergen-induced airway hyperresponsiveness and solubilization of IL-13Rα2.

Results

Among several MMPs tested, only MMP-8 cleaved IL-13Rα2. Treatment of transfected human or murine cells expressing high levels of surface IL-13Rα2 with MMP-8 resulted in release of soluble IL-13Rα2 into the supernatants, with a concomitant decrease in surface IL-13Rα2 levels. The IL-13Rα2 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-13Rα2 protein levels in bronchoalveolar lavage fluid compared with those seen in wild-type mice after house dust mite challenge.

Conclusion

MMP-8 cleaves IL-13Rα2 in vitro and contributes to the solubilization of IL-13Rα2 in vivo.

Section snippets

Animals

Animals were maintained and handled under institutional animal care and use committee–approved procedures. C57BL/6 MMP-8–deficient mice were kindly provided by Dr Steven D. Shapiro (University of Pittsburgh School of Medicine, Pittsburgh, Pa),31 and the wild-type C57BL/6 and FVB/N mice were purchased from Jackson Laboratories (Bar Harbor, Me). HDM (Dermatophagoides pteronyssinus) was purchased from Greer Laboratories (Lenoir, NC). The mice were immunized as previously described.21 Two days

Increased levels of soluble IL-13Rα2 in serum and BALF and MMP expression in lungs in a murine model of asthma

We characterized soluble IL-13Rα2 levels in the serum and BALF in mice sensitized and challenged with HDM. As shown in Fig 1, A and B, the level of soluble IL-13Rα2 was increased in both serum and BALF in HDM-treated mice compared with that seen in PBS-treated mice. To determine the expression of different MMPs in the murine lungs after HDM sensitization and challenge, we performed an RNase protection assay to examine mRNA expression for murine MMPs. As shown in Fig 1, C, HDM sensitization and

Discussion

Soluble cytokine receptors have important roles in the regulation of cell-signaling pathways.37, 38, 39 Shedding of membrane-bound receptors has been shown as a mechanism to generate soluble receptors.24, 25 In this article we demonstrated that soluble IL-13Rα2 can be produced by means of direct cleavage by MMP-8 and that MMP-8 contributes to the solubilization of IL-13Rα2 in BALF in HDM-treated mice.

MMPs have been shown to be important mediators of airway inflammation and remodeling.40 Among

References (49)

  • J.H. Vernooy et al.

    Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD

    Chest

    (2004)
  • K. Prikk et al.

    Airway obstruction correlates with collagenase-2 (MMP-8) expression and activation in bronchial asthma

    Lab Invest

    (2002)
  • M. Matsumura et al.

    Endogenous metalloprotease solubilizes IL-13 receptor alpha2 in airway epithelial cells

    Biochem Biophys Res Commun

    (2007)
  • A. Minty et al.

    Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses

    Nature

    (1993)
  • A.N. McKenzie et al.

    Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function

    Proc Natl Acad Sci U S A

    (1993)
  • Z. Zhu et al.

    Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production

    J Clin Invest

    (1999)
  • S.K. Huang et al.

    IL-13 expression at the sites of allergen challenge in patients with asthma

    J Immunol

    (1995)
  • C. Doucet et al.

    Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma

    J Clin Invest

    (1998)
  • G.K. Hershey

    IL-13 receptors and signaling pathways: an evolving web

    J Allergy Clin Immunol

    (2003)
  • D.D. Donaldson et al.

    The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1

    J Immunol

    (1998)
  • M. Wills-Karp et al.

    Interleukin-13: central mediator of allergic asthma

    Science

    (1998)
  • G. Grunig et al.

    Requirement for IL-13 independently of IL-4 in experimental asthma

    Science

    (1998)
  • N. Wood et al.

    Enhanced interleukin (IL)-13 responses in mice lacking IL-13 receptor alpha 2

    J Exp Med

    (2003)
  • M.G. Chiaramonte et al.

    Regulation and function of the interleukin 13 receptor alpha 2 during a T helper cell type 2-dominant immune response

    J Exp Med

    (2003)
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    Supported by National Institutes of Health grant R01 AI58157 (G.K.K.H.).

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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