Feedback control of cyclooxygenase-2 expression through PPAR gamma

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandins (PG), p lays a key role in inflammation, tumorigenesis, development, and circulator y homeostasis. The POD, metabolite 15-deoxy-Delta(12,14) PGJ(2) (15d-PGJ(2) ) was identified as a potent natural ligand for the peroxisome proliferator -activated receptor-gamma (PPAR gamma), PPAR gamma 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-PGJ(2) suppresses the Lipopolysaccharide (LPS)-indu ced expression of COX-2 in the macrophage-like differentiated U937 cells bu t not in vascular endothelial cells. PPAR gamma mRNA abundantly expressed i n the U937 cells, not in the endothelial cells, is down-regulated by LPS, I n contrast, LPS up-regulates mRNA for the glucocorticoid receptor which lig and anti-inflammatory steroid dexamethasone (DEX) strongly suppresses the L PS-induced expression of COX-2, although both 15d-PGJ(2) and DEX suppressed COX-2 promoter activity by interfering with the NF-kappa B signaling pathw ay, Transfection of a PPAR gamma expression vector into the endothelial cel ls acquires this suppressive regulation of COX-2 gene by 15d-PGJ(2) but not by DM. A selective COX-2 inhibitor, NS-398, inhibits production of PGD(2) in the U937 cells. Taking these findings together, we propose that expressi on of COX-2 is regulated by a negative feedback loop mediated through PPAR gamma, which makes possible a dynamic production of PC, especially in macro phages, and may be attributed to various expression patterns and physiologi cal functions of COX-2.