Matrix metalloproteinase 8 contributes to solubilization of IL-13 receptor alpha2 in vivo.
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.
Chen
Weiguo
W
Division of Allergy and Immunology, Institute for Personalized and Predictive Medicine, Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA.
Tabata
Yasuhiro
Y
Gibson
Aaron M
AM
Daines
Michael O
MO
Warrier
Manoj R
MR
Wills-Karp
Marsha
M
Hershey
Gurjit K Khurana
GK
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
D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D020784:Matrix Metalloproteinase 8