EP2/EP4 signalling inhibits monocyte chemoattractant protein-1 production induced by interleukin 1β in synovial fibroblasts

Background: Besides its proinflammatory properties, prostaglandin E-2 (PGE(2)) acts as a regulator of the expression of inducible genes. Inhibition of PGE(2) synthesis might thus result in a paradoxical deleterious effect on inflammation. Objective: To examine the effect of PGE(2) on monocyte chemoattractant protein-1 (MCP-1) expression in cultured synovial fibroblasts (SF) stimulated with interleukin (IL)1beta. Methods: MCP-1 expression was assessed in SF stimulated with IL1beta in the presence of PGE(2) 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 PGE(2) receptors (EP) in PGE(2) action was assessed employing EP receptor subtype-specific agonists. Results: PGE(2) significantly inhibited IL1beta induced MCP-1 expression in SF in a dose dependent manner. IL1beta increased COX-2 and did not alter COX-1 synthesis in SF. 11-Deoxy-PGE(1), an EP2/EP4 agonist, reproduced PGE(2) action on MCP-1 expression. Butaprost, a selective EP2 agonist, was less potent than PGE(2). Sulprostone, an EP1/EP3 agonist, had no effect on IL1beta induced MCP-1 expression. Inhibition of endogenous PGE(2) synthesis by NSAIDs further enhanced MCP-1 mRNA expression in IL1beta stimulated SF, an effect prevented by addition of exogenous PGE(2). Conclusion: Activation of EP2/EP4 receptors down regulates the expression of MCP-1 in IL1beta stimulated SF, while PGE(2) 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.