Feedback control of cyclooxygenase-2 expression through PPARγ

Abstract

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandins (PG), plays a key role in inflammation, tumorigenesis, development, and circulatory homeostasis. The PGD2 metabolite 15-deoxy-Δ12,14 PGJ2 (15d-PGJ2) was identified as a potent natural ligand for the peroxisome proliferator-activated receptor-γ (PPARγ). PPARγ expressed in macrophages has been postulated as a negative regulator of inflammation and a positive regulator of differentiation into foam cell associated with atherogenesis. Here, we show that 15d-PGJ2 suppresses the lipopolysaccharide (LPS)-induced expression of COX-2 in the macrophage-like differentiated U937 cells but not in vascular endothelial cells. PPARγ mRNA abundantly expressed in the U937 cells, not in the endothelial ceils, is down-regulated by LPS. In contrast, LPS up-regulates mRNA for the glucocorticoid receptor which ligand anti-inflammatory steroid dexamethasone (DEX) strongly suppresses the LPS-induced expression of COX-2, although both 15d-PGJ2 and DEX suppressed COX-2 promoter activity by interfering with the NF-κB signaling pathway. Transfection of a PPARγ expression vector into the endothelial cells acquires this suppressive regulation of COX-2 gene by 15d-PGJ2 but not by DEX. A selective COX-2 inhibitor, NS-398, inhibits production of PGD2 in the U937 cells. Taking these findings together, we propose that expression of COX-2 is regulated by a negative feedback loop mediated through PPARγ, which makes possible a dynamic production of PG, especially in macrophages, and may be attributed to various expression patterns and physiological functions of COX-2.