Objective--15-Deoxy-^12,14-prostaglandin J₂ (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor- (PPAR), has been shown to inhibit proinflammatory gene expression, but the signaling mechanisms involved remain unclear. Because retinoic acid receptor-related orphan receptor- (ROR) has been reported to suppress tumor necrosis factor- (TNF-)-induced expression of proinflammatory genes, we hypothesized that 15d-PGJ2 may induce ROR expression resulting in inhibition of proinflammatory gene expression.

Methods and Results--We demonstrate that 15d-PGJ2 induced ROR1 and ROR4 expression and inhibited TNF--induced vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in human umbilical vein endothelial cells (HUVECs). In contrast, the synthetic PPAR ligand pioglitazone weakly induced ROR4 expression but did not affect ROR1 expression or TNF--induced gene expression. Biphenol A diglycidyl ether, a PPAR antagonist, did not block the effect of 15d-PGJ2 on ROR expression. Adenovirus-mediated overexpression of ROR1 inhibited TNF--induced VCAM-1 and ICAM-1 expression, and overexpression of a mutant form of ROR1 (ROR1), which inhibited transcriptional activity of ROR1 and ROR4, attenuated its inhibition. Furthermore, we found that ROR1 attenuated the inhibitory actions of 15d-PGJ2 on TNF--induced VCAM-1 and ICAM-1 expression.

Conclusions--These results suggest that 15d-PGJ2 inhibits TNF--induced expression of proinflammatory genes mediated in part via induction of ROR in HUVECs. This mechanism provides a novel insight into PPAR-independent actions of 15d-PGJ2.