Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3 |
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Authors: | McQuibban G A Gong J H Tam E M McCulloch C A Clark-Lewis I Overall C M |
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Affiliation: | Department of Biochemistry and Molecular Biology, Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. |
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Abstract: | Tissue degradation by the matrix metalloproteinase gelatinase A is pivotal to inflammation and metastases. Recognizing the catalytic importance of substrate-binding exosites outside the catalytic domain, we screened for extracellular substrates using the gelatinase A hemopexin domain as bait in the yeast two-hybrid system. Monocyte chemoattractant protein-3 (MCP-3) was identified as a physiological substrate of gelatinase A. Cleaved MCP-3 binds to CC-chemokine receptors-1, -2, and -3, but no longer induces calcium fluxes or promotes chemotaxis, and instead acts as a general chemokine antagonist that dampens inflammation. This suggests that matrix metalloproteinases are both effectors and regulators of the inflammatory response. |
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