title: Effect of peroxisome proliferator activated receptor (PPAR)gamma agonists on prostaglandins cascade in joint cells.
abstract: In response to inflammatory cytokines, chondrocytes and synovial fibroblasts produce high amounts of prostaglandins (PG) which self-perpetuate locally the inflammatory reaction. Prostaglandins act primarily through membrane receptors coupled to G proteins but also bind to nuclear Peroxisome Proliferator-Activated Receptors (PPARs). Amongst fatty acids, the cyclopentenone metabolite of PGD2, 15-deoxy-Delta12,14PGJ2 (15d-PGJ2), was shown to be a potent ligand of the PPARgamma isotype prone to inhibit the production of inflammatory mediators. As the stimulated synthesis of PGE2 originates from the preferential coupling of inducible enzymes, cyclooxygenase-2 (COX-2) and membrane PGE synthase-1 (mPGES-1), we investigated the potency of 15d-PGJ2 to regulate prostaglandins synthesis in rat chondrocytes stimulated with interleukin-1beta (IL-1beta). We demonstrated that 15d-PGJ2, but not the high-affinity PPARgamma ligand rosiglitazone, decreased almost completely PGE2 synthesis and mPGES-1 expression. The inhibitory potency of 15d-PGJ2 was unaffected by changes in PPARgamma expression and resulted from inhibition of NF-kappaB nuclear binding and IkappaBalpha sparing, secondary to reduced phosphorylation of IKKbeta. Consistently with 15d-PGJ2 being a putative endogenous regulator of the inflammatory reaction if synthesized in sufficient amounts, the present data confirm the variable PPARgamma-dependency of its effects in joint cells while underlining possible species and cell types specificities.
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Articulaires, UMR 7561 CNRS-UHP, Nancy, France.
authors.forename: David
authors.initials: D
authors.lastname: Moulin
authors.forename: Paul-Emile
authors.initials: PE
authors.lastname: Poleni
authors.forename: Mélanie
authors.initials: M
authors.lastname: Kirchmeyer
authors.forename: Sylvie
authors.initials: S
authors.lastname: Sebillaud
authors.forename: Meriem
authors.initials: M
authors.lastname: Koufany
authors.forename: Patrick
authors.initials: P
authors.lastname: Netter
authors.forename: Bernard
authors.initials: B
authors.lastname: Terlain
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bianchi
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Jouzeau
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists* / Q000502:physiology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007375:Interleukin-1; D016328:NF-kappa B; D047495:PPAR gamma; D011453:Prostaglandins; D015232:Dinoprostone; D015230:Prostaglandin D2