Matrix metalloproteinase-dependent microsomal prostaglandin E synthase-1 expression in macrophages: role of TNF-α and the EP4 prostanoid receptor.

TitleMatrix metalloproteinase-dependent microsomal prostaglandin E synthase-1 expression in macrophages: role of TNF-α and the EP4 prostanoid receptor.
Publication TypeJournal Article
Year of Publication2012
AuthorsKhan KMFaisal, Kothari P, Du B, Dannenberg AJ, Falcone DJ
JournalJ Immunol
Volume188
Issue4
Pagination1970-80
Date Published2012 Feb 15
ISSN1550-6606
KeywordsAnimals, Cells, Cultured, Cyclooxygenase 2, Early Growth Response Protein 1, Intramolecular Oxidoreductases, Macrophages, Matrix Metalloproteinase 1, Matrix Metalloproteinase 3, Matrix Metalloproteinase 9, Mice, Prostaglandin-E Synthases, Receptors, Prostaglandin E, EP4 Subtype, RNA Interference, RNA, Small Interfering, Signal Transduction, Tumor Necrosis Factor-alpha
Abstract

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.

DOI10.4049/jimmunol.1102383
Alternate JournalJ Immunol
PubMed ID22227567
Grant ListHL093331 / HL / NHLBI NIH HHS / United States
Related Faculty: 
Domenick J. Falcone, Ph.D.

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