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EP2/EP4 signalling inhibits monocyte chemoattractant protein-1 production induced by interleukin 1β in synovial fibroblasts
  1. R Largo,
  2. I Díez-Ortego,
  3. O Sanchez-Pernaute,
  4. M J López-Armada,
  5. M A Alvarez-Soria,
  6. J Egido,
  7. G Herrero-Beaumont
  1. Bone and Joint Research Unit, Fundación Jiménez Díaz, Autonoma University, Madrid, Spain
  1. Correspondence to:
    Dr G Herrero-Beaumont
    Rheumatology Department, Fundación Jiménez Díaz, Avenida Reyes Católicos 2, 28040 Madrid, Spain,


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.

  • 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

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