Targeting prostaglandin E2 receptors as an alternative strategy to block cyclooxygenase-2-dependent extracellular matrix-induced matrix metalloproteinase-9 expression by macrophages.

Pavlovic S, Du B, Sakamoto K, Khan KM, Natarajan C, Breyer RM, Dannenberg AJ, Falcone DJ
J Biol Chem. 2006 281 (6): 3321-8

PMID: 16338931 · DOI:10.1074/jbc.M506846200

COX-2-dependent prostaglandin (PG) E2 synthesis regulates macrophage MMP expression, which is thought to destabilize atherosclerotic plaques. However, the administration of selective COX-2 inhibitors paradoxically increases the frequency of adverse cardiovascular events potentially through the loss of anti-inflammatory prostanoids and/or disturbance in the balance of pro- and anti-thrombotic prostanoids. To avoid these collateral effects of COX-2 inhibition, a strategy to identify and block specific prostanoid-receptor interactions may be required. We previously reported that macrophage engagement of vascular extracellular matrix (ECM) triggers proteinase expression through a MAPKerk1/2-dependent increase in COX-2 expression and PGE2 synthesis. Here we demonstrate that elicited macrophages express the PGE2 receptors EP1-4. When plated on ECM, their expression of EP2 and EP4, receptors linked to PGE2-induced activation of adenylyl cyclase, is strongly stimulated. Forskolin and dibutryl cyclic-AMP stimulate macrophage matrix metalloproteinase (MMP)-9 expression in a dose-dependent manner. However, an EP2 agonist (butaprost) has no effect on MMP-9 expression, and macrophages from EP2 null mice exhibited enhanced COX-2 and MMP-9 expression when plated on ECM. In contrast, the EP4 agonist (PGE1-OH) stimulated macrophage MMP-9 expression, which was inhibited by the EP4 antagonist ONO-AE3-208. When compared with COX-2 silencing by small interfering RNA or inhibition by celecoxib, the EP4 antagonist was as effective in inhibiting ECM-induced proteinase expression. In addition, ECM-induced MMP-9 expression was blocked in macrophages in which EP4 was silenced by small interfering RNA. Thus, COX-2-dependent ECM-induced proteinase expression is effectively blocked by selective inhibition of EP4, a member of the PGE2 family of receptors.

MeSH Terms (27)

Animals Blotting, Western Bucladesine Celecoxib Cell Line Colforsin Cyclooxygenase 2 Extracellular Matrix Gene Silencing Macrophages MAP Kinase Signaling System Matrix Metalloproteinase 9 Mice Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Naphthalenes Oligonucleotides Peritoneum Phenylbutyrates Phosphorylation Pyrazoles Receptors, Prostaglandin E Reverse Transcriptase Polymerase Chain Reaction RNA, Small Interfering Sulfonamides Time Factors Transfection

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