Matrix metalloproteinases regulate macrophage COX‐2 expression: Role of proteinase activated receptor‐1

Abstract

Matrix metalloproteinases (MMPs) are potent modulators of the inflammatory response. In addition to the extracellular matrix, MMP substrates include growth factors, cytokines, chemokines and receptors. We recently reported that binding of PGE2 to the EP4 prostanoid receptor stimulates macrophage MMP-9 expression, and COX-2 expression via a positive feedback loop. To determine whether COX-2 expression is modulated by extracellular MMPs, murine macrophages were incubated with active MMP-1, 2, 3, 7 or 9. Both MMP-1 and 3 stimulated macrophage COX-2 expression in a dose-dependent manner. In contrast, MMP-2, 7 and 9 had no effect. Up-regulation of COX-2 expression required catalytically active MMP-1 or 3, since expression was not stimulated by pro-MMPs, and the induction of COX-2 observed with active MMPs was blocked by specific MMP-inhibitors. MMP-induced COX-2 was associated with an increase in PGE2 secretion and MMP-9 expression, which were blocked by the selective COX-2 inhibitor, celecoxib. It has been reported that MMP-1 cleaves PAR-1, and initiates PAR-1-dependent signaling. To determine whether the activation of PAR-1 leads to induction of COX-2 and MMP-9, macrophages were incubated with SFFLR, a peptide corresponding to the PAR-1 tethered ligand exposed by proteolysis. The specific PAR-1 agonist stimulated COX-2 and MMP-9 expression; whereas, PAR-2–4 peptide agonists failed to induce COX-2 or MMP-9. Together, these data suggest a regulatory mechanism whereby cleavage of the protease sensor PAR-1 by either MMP-1 or 3 stimulates macrophage MMP-9 expression via a COX-2-dependent pathway. These studies were supported by NIH grant HL073375.