Matrix metalloproteinase (MMP)‐1 and MMP‐3 induced macrophage MMP‐9: Evidence for the role of microsomal prostaglandin synthase (mPGES)‐1

Macrophage MMP‐9 expression has been implicated in the pathogenesis of occlusive and aneurysmal vascular diseases. Previously, we defined a mechanism by which MMP‐1 and MMP‐3 stimulate macrophage MMP‐9 expression via the liberation of TNF‐α and subsequent modulation of the COX‐2→PGE 2 →EP4 receptor axis. In these studies, we determined whether MMP‐induced COX‐2 expression is coupled to expression of a family of PGE synthases, which convert COX‐derived PGH 2 to PGE 2 . Results demonstrate that MMP‐1 and MMP‐3 selectively induced mPGES‐1 expression in macrophages, which was blocked when cells were incubated with anti‐TNF‐α IgG or transfected with TNF‐α siRNA. Treatment of cells with PGE 2 or EP4 agonist PGE 1 ‐OH resulted in rapid phosphorylation of MAPK erk1/2 , increased Egr‐1 and mPGES‐1 expression. PGE 2 failed to induce Egr‐1 or mPGES‐1 expression in cells incubated with the EP4 antagonist AH23848. To determine whether COX‐2→PGE 2 →EP4 contributes to a feedback loop that regulates MMP‐induced mPGES‐1 expression, cells were pre‐incubated with celecoxib, a selective COX‐2 inhibitor, or AH23848. Both celecoxib and AH23848 attenuated MMP‐induced mPGES‐1 expression. Finally, MMP‐1 and MMP‐3 induced MMP‐9 expression was markedly reduced in cells transfected with mPGES‐1 siRNA. Thus, mPGES‐1 is a therapeutic target to regulate MMP‐9 expression in vascular disease. These studies were supported by NHLBI HL093331.