EXTENDED REPORT

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

R Largo, I Díez-Ortego, O Sanchez-Pernaute, M J López-Armada, M A Alvarez-Soria, J Egido, G Herrero-Beaumont

Bone and Joint Research Unit, Fundación Jiménez Díaz, Autonoma University, Madrid, Spain

Correspondence to:
Correspondence to:
Dr G Herrero-Beaumont
Rheumatology Department, Fundación Jiménez Díaz, Avenida Reyes Católicos 2, 28040 Madrid, Spain, gherrero{at}fjd.es

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)1ß.

Methods: MCP-1 expression was assessed in SF stimulated with IL1ß 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 IL1ß induced MCP-1 expression in SF in a dose dependent manner. IL1ß 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 IL1ß induced MCP-1 expression. Inhibition of endogenous PGE₂ synthesis by NSAIDs further enhanced MCP-1 mRNA expression in IL1ß stimulated SF, an effect prevented by addition of exogenous PGE₂.

Conclusion: Activation of EP₂/EP₄ receptors down regulates the expression of MCP-1 in IL1ß 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.

Abbreviations: 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

Keywords: EP2/EP4 receptors; monocyte chemoattractant protein-1; prostaglandin E2; synovial cells

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