TY - JOUR T1 - EP<sub>2</sub>/EP<sub>4</sub> signalling inhibits monocyte chemoattractant protein-1 production induced by interleukin 1β in synovial fibroblasts JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 1197 LP - 1204 DO - 10.1136/ard.2003.011163 VL - 63 IS - 10 AU - R Largo AU - I Díez-Ortego AU - O Sanchez-Pernaute AU - M J López-Armada AU - M A Alvarez-Soria AU - J Egido AU - G Herrero-Beaumont Y1 - 2004/10/01 UR - http://ard.bmj.com/content/63/10/1197.abstract N2 - Background: Besides its proinflammatory properties, prostaglandin E2 (PGE2) acts as a regulator of the expression of inducible genes. Inhibition of PGE2 synthesis might thus result in a paradoxical deleterious effect on inflammation.Objective: To examine the effect of PGE2 on monocyte chemoattractant protein-1 (MCP-1) expression in cultured synovial fibroblasts (SF) stimulated with interleukin (IL)1β.Methods: MCP-1 expression was assessed in SF stimulated with IL1β in the presence of PGE2 or different NSAIDs by RT-PCR or northern blot and immunocytochemistry. Expression of cyclo-oxygenase (COX) isoforms was studied by western blot techniques. The role of PGE2 receptors (EP) in PGE2 action was assessed employing EP receptor subtype-specific agonists.Results: PGE2 significantly inhibited IL1β induced MCP-1 expression in SF in a dose dependent manner. IL1β increased COX-2 and did not alter COX-1 synthesis in SF. 11-Deoxy-PGE1, an EP2/EP4 agonist, reproduced PGE2 action on MCP-1 expression. Butaprost, a selective EP2 agonist, was less potent than PGE2. Sulprostone, an EP1/EP3 agonist, had no effect on IL1β induced MCP-1 expression. Inhibition of endogenous PGE2 synthesis by NSAIDs further enhanced MCP-1 mRNA expression in IL1β stimulated SF, an effect prevented by addition of exogenous PGE2.Conclusion: Activation of EP2/EP4 receptors down regulates the expression of MCP-1 in IL1β stimulated SF, while PGE2 pharmacological inhibition cuts off this signalling pathway and results in a superinduction of MCP-1 expression. The data suggest that NSAIDs may intercept a natural regulatory circuit controlling the magnitude of inflammation, which questions their continuous administration in inflammatory joint diseases. ER -