15‐Deoxy‐Δ12,14‐prostaglandin J2 inhibits IL‐1β‐induced IKK enzymatic activity and IκBα degradation in rat chondrocytes through a PPARγ‐independent pathway

Peroxisome proliferator-activated receptor γ (PPARγ) ligands have been shown to inhibit the effects of proinflammatory cytokines such as interleukin-1β (IL-1β). This cytokine plays a key role in articular pathophysiologies by inducing the production of inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2). We previously demonstrated that 15d-PGJ2 was more potent than troglitazone to counteract IL-1β effects on chondrocytes. Here, we studied the action of 15d-PGJ2 on intracellular targets in nuclear factor-κB (NF-κB) signalling pathway in IL-1β treated rat chondrocytes. We found that 15d-PGJ2 decreased inhibitor κBα (IκBα) degradation but not its phosphorylation by specifically inhibiting IκB kinase β (IKKβ), but not IKKα, enzymatic activity. We further evaluated the involvement of PPARγ in the anti-inflammatory action of its ligands. In chondrocytes overexpressing functional PPARγ protein, 15d-PGJ2 pre-treatment inhibited inducible NO synthase and COX-2 mRNA expression, nitrite and PGE2 production, p65 translocation and NF-κB activation. Troglitazone or rosiglitazone pre-treatment had no effect. 15d-PGJ2 exhibited the same effect in chondrocytes overexpressing mutated PPARγ protein. These results suggest that 15d-PGJ2 exerts its anti-inflammatory effect in rat chondrocytes by a PPARγ-independent mechanism, which can be conferred to a partial inhibition of IκBα degradation.