Inflammation Dampened by Gelatinase A Cleavage of Monocyte Chemoattractant Protein-3
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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We thank G. Pelman for synovial fluid samples. Supported by a grant from the National Cancer Institute of Canada (NCIC), with funds provided in part by the Canadian Cancer Society, and by Medical Research Council Group grant funding. G.A.M. is supported by a NCIC studentship.
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Published In
Science
Volume 289 | Issue 5482
18 August 2000
18 August 2000
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Received: 2 May 2000
Accepted: 30 June 2000
Published in print: 18 August 2000
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- G. Angus McQuibban et al.
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