15-deoxy-Delta(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats

Peroxisome proliferator-activated receptors (PPARs) are members of the nucl ear hormone receptor superfamily and have a dominant regulatory role in adi pocyte and monocyte differentiation. PPAR-gamma agonists are also negative regulators of macrophage activation and have modulatory effects on tumorige nesis. In this study we demonstrate that synovial tissue localized expressi on of PPAR-gamma in patients with rheumatoid arthritis (RA). We detected ma rkedly enhanced expression of PPAR-gamma in macrophages, as well as modestl y enhanced expression in the synovial lining layer, fibroblasts, and endoth elial cells. Activation of the PPAR-gamma by 15-deoxy-Delta(12,14)-prostagl andin J(2) (15d-PGJ(2)) and the synthetic PPAR-gamma ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal admini stration of these PPAR-gamma ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Antiinflammatory effects of 15d-PGJ(2) were more potent than troglitazone. These findings suggest that PPAR-gamma may be an importa nt immunoinflammatory mediator and its ligands, especially 15d-PGJ(2), may be useful in the treatment of RA.