enzymatic activity and IjBa degradation in rat chondrocytes through a PPARc-independent pathway

Peroxisome proliferator-activated receptorc (PPARc) ligands have been shown to inhibit the effects of proinflammatory cytokines such as interleukin-1b (IL-1b). This cytokine plays a key role in articular pathophysiologies by inducing the production of inflammatory mediators such as nitric oxide (NO) and prostaglan- din E2 (PGE2). We previously demonstrated that 15d-PGJ2 was more potent than troglitazone to counteract IL-1b effects on chondrocytes. Here, we studied the action of 15d-PGJ2 on intracellular targets in nuclear factor-jB (NF-jB) signalling pathway in IL-1b treated rat chondrocytes. We found that 15d- PGJ2 decreased inhibitor jBa (IjBa) degradation but not its phosphorylation by specifically inhibiting IjB kinaseb (IKKb), but not IKKa, enzymatic activity. We further evaluated the involve- ment of PPARc in the anti-inflammatory action of its ligands. In chondrocytes overexpressing functional PPARc protein, 15d- PGJ2 pre-treatment inhibited inducible NO synthase and COX-2 mRNA expression, nitrite and PGE2 production, p65 translocation and NF-jB activation. Troglitazone or rosiglitazone pre-treatment had no effect. 15d-PGJ2 exhibited the same effect in chondrocytes overexpressing mutated PPARc protein. These results suggest that 15d-PGJ2 exerts its anti-inflammatory effect in rat chondrocytes by a PPARc-independent mechanism, which can be conferred to a partial inhibition of IjBa degradation. 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.