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MMP‐1 and MMP‐3 stimulate macrophage MMP‐9 expression by upregulating components of the PGE 2 biosynthetic pathway
Author(s) -
Khan K.M. Faisal,
Steenport Michel L.,
Du Baoheng,
Dannenberg Andrew J.,
Falcone Domenick J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.903.3
Subject(s) - prostaglandin e2 receptor , matrix metalloproteinase , agonist , prostaglandin e , receptor , macrophage , chemistry , downregulation and upregulation , endocrinology , medicine , biology , biochemistry , in vitro , gene
Evidence has implicated MMP‐9 expression with the pathogenesis of occlusive and aneurysmal vascular diseases. In previous studies, we characterized a COX‐2→PGE 2 →EP4 receptor axis that regulates macrophage MMP‐9 expression. In the current studies, we determined whether MMPs in the inflammatory environment regulate expression of COX‐2→PGE 2 →EP4 receptor axis components. Results demonstrate that active MMP‐1 and MMP‐3 induce macrophage COX‐2 expression, which led to increased secretion of PGE 2 , PGE 2 →EP4 and subsequent MMP‐9 expression. MMP‐induced COX‐2 expression was coupled with increased expression of microsomal PGE synthase‐1 (mPGES‐1). Since COX‐2 expression is enhanced by PGE 2 via an EP4‐dependent feedback loop, we determined whether PGE 2 →EP4 regulated levels of mPGES‐1. MMP‐1 and MMP‐3 selectively up‐regulated macrophage expression of PGE 2 receptors, EP2 and EP4. Negligible levels of mPGES‐1 were observed in control macrophages and cells incubated with the EP2 agonist butaprost. In contrast, both PGE 2 and the EP4 agonist PGE 1 ‐OH stimulated mPGES‐1 expression, and PGE 2 failed to induce mPGES‐1 expression in cells incubated with the EP4 antagonist ONO‐AE3‐208. Thus, MMPs regulate macrophage MMP‐9 expression by up‐regulating components of the PGE 2 biosynthetic pathway. These studies were supported by HL073375 and the Center for Cancer Prevention Research.