TY - JOUR
T1 - Matrix metalloproteinase-dependent microsomal prostaglandin E synthase-1 expression in macrophages
T2 - Role of tnf-α and the EP4 prostanoid receptor
AU - Khan, K. M.Faisal
AU - Kothari, Poonam
AU - Du, Baoheng
AU - Dannenberg, Andrew J.
AU - Falcone, Domenick J.
N1 - Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2012/2/15
Y1 - 2012/2/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1102383
DO - 10.4049/jimmunol.1102383
M3 - Article
C2 - 22227567
AN - SCOPUS:84856829089
VL - 188
SP - 1970
EP - 1980
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 4
ER -