| First Author | Khan KM | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 4 | Pages | 1970-80 |
| PubMed ID | 22227567 | Mgi Jnum | J:181219 |
| Mgi Id | MGI:5309084 | Doi | 10.4049/jimmunol.1102383 |
| Citation | Khan KM, et al. (2012) Matrix metalloproteinase-dependent microsomal prostaglandin E synthase-1 expression in macrophages: role of TNF-alpha and the EP4 prostanoid receptor. J Immunol 188(4):1970-80 |
| abstractText | 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-alpha 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-alpha 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. |
