Effect of Peroxisome Proliferator Activated Receptor (PPAR)γ agonists on prostaglandins cascade in joint cells

摘要

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 PGD_2, 15-deoxy-Δ~(12,14)PGJ_2 (15d-PGJ_2), was shown to be a potent ligand of the PPARγ isotype prone to inhibit the production of inflammatory mediators. As the stimulated synthesis of PGE_2 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-PGJ_2 to regulate prostaglandins synthesis in rat chondrocytes stimulated with interleukin-1β (IL-1β). We demonstrated that 15d-PGJ_2, but not the high-affinity PPARγ ligand rosiglitazone, decreased almost completely PGE_2 synthesis and mPGES-1 expression. The inhibitory potency of 15d-PGJ_2 was unaffected by changes in PPARγ expression and resulted from inhibition of NF-κB nuclear binding and IκBα sparing, secondary to reduced phosphorylation of IKKβ. Consistently with 15d-PGJ_2 being a putative endogenous regulator of the inflammatory reaction if synthesized in sufficient amounts, the present data confirm the variable PPARγ-dependency of its effects in joint cells while underlining possible species and cell types specificities.