Matrix metalloproteinase-dependent microsomal prostaglandin E synthase-1 expression in macrophages: role of TNF-α and the EP4 prostanoid receptor.
Matrix metalloproteinase (MMP)-9 contributes to the pathogenesis of chronic inflammatory diseases and cancer. Thus, identifying targetable components of signaling pathways that regulate MMP-9 expression may have broad therapeutic implications. Our previous studies revealed a nexus between metalloproteinases and prostanoids whereby MMP-1 and MMP-3, commonly found in inflammatory and neoplastic foci, stimulate macrophage MMP-9 expression via the release of TNF-α and subsequent induction of cyclooxygenase-2 and PGE(2) engagement of EP4 receptor. In the current study, we determined whether MMP-induced cyclooxygenase-2 expression was coupled to the expression of prostaglandin E synthase family members. We found that MMP-1- and MMP-3-dependent release of TNF-α induced rapid and transient expression of early growth response protein 1 in macrophages followed by sustained elevation in microsomal prostaglandin synthase 1 (mPGES-1) expression. Metalloproteinase-induced PGE(2) levels and MMP-9 expression were markedly attenuated in macrophages in which mPGES-1 was silenced, thereby identifying mPGES-1 as a therapeutic target in the regulation of MMP-9 expression. Finally, the induction of mPGES-1 was regulated, in part, through a positive feedback loop dependent on PGE(2) binding to EP4. Thus, in addition to inhibiting macrophage MMP-9 expression, EP4 antagonists emerge as potential therapy to reduce mPGES-1 expression and PGE(2) levels in inflammatory and neoplastic settings.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
K M Faisal
KM
Khan
Poonam
P
Kothari
Baoheng
B
Du
Andrew J
AJ
Dannenberg
Domenick J
DJ
Falcone
D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D000071876:Prostaglandin-E Synthases; D034622:RNA Interference; D034741:RNA, Small Interfering; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051766:Early Growth Response Protein 1; D034741:RNA, Small Interfering; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse