Hideyuki Migita1, John Morser. 1. Department of Pharmacology, Berlex Biosciences, Richmond, CA 94806, USA. hideyuki_migita@berlex.com
Abstract
OBJECTIVE: 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-gamma (PPARgamma), has been shown to inhibit proinflammatory gene expression, but the signaling mechanisms involved remain unclear. Because retinoic acid receptor-related orphan receptor-alpha (RORalpha) has been reported to suppress tumor necrosis factor-alpha (TNF-alpha)-induced expression of proinflammatory genes, we hypothesized that 15d-PGJ2 may induce RORalpha expression resulting in inhibition of proinflammatory gene expression. METHODS AND RESULTS: We demonstrate that 15d-PGJ2 induced RORalpha1 and RORalpha4 expression and inhibited TNF-alpha-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 PPARgamma ligand pioglitazone weakly induced RORalpha4 expression but did not affect RORalpha1 expression or TNF-alpha-induced gene expression. Biphenol A diglycidyl ether, a PPARgamma antagonist, did not block the effect of 15d-PGJ2 on RORalpha expression. Adenovirus-mediated overexpression of RORalpha1 inhibited TNF-alpha-induced VCAM-1 and ICAM-1 expression, and overexpression of a mutant form of RORalpha1 (RORalpha1Delta), which inhibited transcriptional activity of RORalpha1 and RORalpha4, attenuated its inhibition. Furthermore, we found that RORalpha1Delta attenuated the inhibitory actions of 15d-PGJ2 on TNF-alpha-induced VCAM-1 and ICAM-1 expression. CONCLUSIONS: These results suggest that 15d-PGJ2 inhibits TNF-alpha-induced expression of proinflammatory genes mediated in part via induction of RORalpha in HUVECs. This mechanism provides a novel insight into PPARgamma-independent actions of 15d-PGJ2.
OBJECTIVE: 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-gamma (PPARgamma), has been shown to inhibit proinflammatory gene expression, but the signaling mechanisms involved remain unclear. Because retinoic acid receptor-related orphan receptor-alpha (RORalpha) has been reported to suppress tumor necrosis factor-alpha (TNF-alpha)-induced expression of proinflammatory genes, we hypothesized that 15d-PGJ2 may induce RORalpha expression resulting in inhibition of proinflammatory gene expression. METHODS AND RESULTS: We demonstrate that 15d-PGJ2 induced RORalpha1 and RORalpha4 expression and inhibited TNF-alpha-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 PPARgamma ligand pioglitazone weakly induced RORalpha4 expression but did not affect RORalpha1 expression or TNF-alpha-induced gene expression. Biphenol A diglycidyl ether, a PPARgamma antagonist, did not block the effect of 15d-PGJ2 on RORalpha expression. Adenovirus-mediated overexpression of RORalpha1 inhibited TNF-alpha-induced VCAM-1 and ICAM-1 expression, and overexpression of a mutant form of RORalpha1 (RORalpha1Delta), which inhibited transcriptional activity of RORalpha1 and RORalpha4, attenuated its inhibition. Furthermore, we found that RORalpha1Delta attenuated the inhibitory actions of 15d-PGJ2 on TNF-alpha-induced VCAM-1 and ICAM-1 expression. CONCLUSIONS: These results suggest that 15d-PGJ2 inhibits TNF-alpha-induced expression of proinflammatory genes mediated in part via induction of RORalpha in HUVECs. This mechanism provides a novel insight into PPARgamma-independent actions of 15d-PGJ2.