EP2/EP4 signalling inhibits monocyte chemoattractant protein-1 production induced by interleukin 1β in synovial fibroblasts. Issue 10 (10th September 2004)

• Record Type: Journal Article
• Authors: Largo, R; Díez-Ortego, I; Sanchez-Pernaute, O; López-Armada, M J; Alvarez-Soria, M A; Egido, J; Herrero-Beaumont, G
• Is Part Of: Annals of the rheumatic diseases. Volume 63:Issue 10(2004)
• Page Start: 1197
• Page End: 1204
• Publication Date: 2004-09-10
• Subjects: AC, adenylate cyclase -- cAMP, cyclic adenosine monophosphate -- COX, cyclo-oxygenase -- DCF, diclofenac -- EMSA, electrophoretic mobility shift assay -- GAPDH, glyceraldehyde-3′-phosphate dehydrogenase -- IL, interleukin -- MCP-1, monocyte chemoattractant peptide-1 -- MXC, meloxicam -- NSAIDs, non-steroidal anti-inflammatory drugs -- PGE2, prostaglandin E2 -- RT-PCR, reverse transcription-polymerase chain reaction -- SF, synovial fibroblasts; EP2/EP4 receptors -- monocyte chemoattractant protein-1 -- prostaglandin E2 -- synovial cells; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/ard.2003.011163
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : 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.