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

Autor: Gabriel Herrero-Beaumont, Olga Sánchez-Pernaute, Raquel Largo, Jesús Egido, M J López-Armada, I Díez-Ortego, M A Alvarez-Soria
Jazyk: angličtina
Rok vydání: 2004
Předmět:
Agonist
medicine.medical_specialty
medicine.drug_class
Prostaglandin E2 receptor
medicine.medical_treatment
Immunology
General Biochemistry
Genetics and Molecular Biology
Dinoprostone
Proinflammatory cytokine
Rheumatology
Internal medicine
medicine
Immunology and Allergy
Animals
Humans
Receptors
Prostaglandin E
Northern blot
RNA
Messenger
Receptor
Cells
Cultured
Chemokine CCL2
Dose-Response Relationship
Drug
business.industry
Anti-Inflammatory Agents
Non-Steroidal
Synovial Membrane
NF-kappa B
Interleukin
Fibroblasts
Receptors
Prostaglandin E
EP2 Subtype
Recombinant Proteins
Extended Report
Endocrinology
Gene Expression Regulation
lipids (amino acids
peptides
and proteins)
Rabbits
Signal transduction
business
Receptors
Prostaglandin E
EP4 Subtype
Prostaglandin E
Interleukin-1
Signal Transduction
Popis: 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)1β. Methods: MCP-1 expression was assessed in SF stimulated with IL1β 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 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-PGE 1 , an EP 2 /EP 4 agonist, reproduced PGE 2 action on MCP-1 expression. Butaprost, a selective EP 2 agonist, was less potent than PGE 2 . Sulprostone, an EP 1 /EP 3 agonist, had no effect on IL1β induced MCP-1 expression. Inhibition of endogenous PGE 2 synthesis by NSAIDs further enhanced MCP-1 mRNA expression in IL1β stimulated SF, an effect prevented by addition of exogenous PGE 2 . Conclusion: Activation of EP 2 /EP 4 receptors down regulates the expression of MCP-1 in IL1β 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.
Databáze: OpenAIRE
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