Rosiglitazone Induces Interleukin-1 Receptor Antagonist in Interleukin-1β-Stimulated Rat Synovial Fibroblasts via a Peroxisome Proliferator-Activated Receptor β/δ-Dependent Mechanism

Objective. To study the potency of 2 peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, 15-deoxy-Delta(12,14)-prostagiandin J(2) (15-deoxy-PGJ(2)) and rosiglitazone, to modulate the expression of interleukin-1 receptor antagonist (IL-IRa) in rat synovial fibroblasts. Methods. Levels of messenger RNA for IL-IRa and PPAR isotypes (alpha, beta/delta, gamma) were assessed by real-time polymerase chain reaction in rat synovial fibroblasts exposed to 10 ng/ml of IL-1 beta. PPAR levels were assessed by Western blotting and secreted IL-IRa levels by immunoassay. The potency of PPAR gamma agonists and the PPAR beta/delta agonist GW-501516 on IL-IRa levels was tested in the range of 1-10 mu M and at 100 pM, respectively. The contribution of PPAR gamma to the effects of rosiglitazone on IL-IRa secretion was examined either by its overexpression or by inhibition using wild-type or dominant-negative constructs and the antagonist GW-9662 (10 mu M), respectively. The dominant-negative strategy was also performed to investigate the possible contribution of PPAR beta/delta and NF-kappa B activation. Results. IL-1 beta-induced IL-IRa production was increased by 10 mu M rosiglitazone but was reduced dose-dependently by 15-deoxy-PGJ(2). Both agonists lowered IL-1 beta secretion, but rosiglitazone alone reduced the imbalance of IL-1 beta/IL-1Ra toward basal levels. Enhancement of IL-1 beta-induced IL-IRa production by rosiglitazone was not affected by PPAR gamma overexpression or by its inhibition with dominant-negative PPAR gamma or GW-9662. Inhibition of NF-kappa B was also ineffective against rosiglitazone but abolished the stimulating effect of IL-1 beta on IL-1Ra. All PPAR isotypes were expressed constitutively in rat synoviocytes, but PPAR gamma decreased dramatically upon IL-1 beta exposure, whereas PPAR beta/delta remained stable. Dominant-negative PPAR beta/delta abolished the enhancement of IL-1Ra by rosiglitazone, whereas GW-501516 reproduced the effect of rosiglitazone on IL-1Ra secretion. Conclusion. Rosiglitazone stimulates IL-1Ra production by a PPAR beta/delta mechanism in activated rat synovial fibroblasts, further contributing to its potential antiarthritic properties and opening new perspectives for the modulation of inflammatory genes by specific PPAR agonists in articular cells.