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

K. M.Faisal Khan, Poonam Kothari, Baoheng Du, Andrew J. Dannenberg, Domenick J. Falcone

Research output: Contribution to journalArticle

14 Scopus citations

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 2levels 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.

Original languageEnglish (US)
Pages (from-to)1970-1980
Number of pages11
JournalJournal of Immunology
Volume188
Issue number4
DOIs
StatePublished - Feb 15 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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