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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:710.)
© 2005 American Heart Association, Inc.

Vascular Biology

15-Deoxy-^12,14-Prostaglandin J₂ (15d-PGJ2) Signals Through Retinoic Acid Receptor–Related Orphan Receptor- but Not Peroxisome Proliferator–Activated Receptor- in Human Vascular Endothelial Cells

The Effect of 15d-PGJ2 on Tumor Necrosis Factor-–Induced Gene Expression

Hideyuki Migita; John Morser

From the Department of Pharmacology (H.M.), Berlex Biosciences, Richmond, Calif; and Regenerative Medicine (H.M., J.M.),, Nihon Schering Research Center, Kobe, Japan.

Correspondence to Hideyuki Migita, Department of Pharmacology, Berlex Biosciences, Richmond, CA 94806. E-mail hideyuki_migita{at}berlex.com

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.

15-Deoxy-^12,14-PG J₂ (15d-PGJ2) inhibits proinflammatory gene expression, but its signaling mechanisms remain unclear. Because retinoic acid receptor–related orphan receptor- (ROR) suppresses proinflammatory gene expression, we hypothesized that 15d-PGJ2 induces ROR expression, resulting in inhibition of proinflammatory gene expression. Our results provide a novel insight into anti-inflammatory actions of 15d-PGJ2.

Key Words: 15-deoxy-^12,14-prostaglandin J₂ • retinoic acid receptor–related orphan receptor- • peroxisome proliferator–activated receptor- • endothelium • inflammation

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