Inflammation dampened by gelatinase A cleavage of monocyte chemoattractantprotein-3

Tissue degradation by the matrix metalloproteinase gelatinase A is pivotal to inflammation and metastases. Recognizing the catalytic importance of sub strate-binding exosites outside the catalytic domain, we screened for extra cellular substrates using the gelatinase A hemopexin domain as bait in the yeast two-hybrid system. Monocyte chemoattractant protein-3 (MCP-3) was ide ntified as a physiological substrate of gelatinase A. Cleaved MCP-3 binds t o CC-chemokine receptors-1, -2, and -3, but no Longer induces calcium fluxe s or promotes chemotaxis, and instead acts as a general chemokine antagonis t that dampens inflammation. This suggests that matrix metalloproteinases a re both effecters and regulators of the inflammatory response.