Feedback control of cyclooxygenase-2 expression through PPARgamma

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandins (PG), plays a key role in inflammation, tumorigenesis, development, and circulatory homeostasis. The PGD(2) 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 (PPARgamma). PPARgamma 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)-induced expression of COX-2 in the macrophage-like differentiated U937 cells but not in vascular endothelial cells. PPARgamma mRNA abundantly expressed in the U937 cells, not in the endothelial cells, 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-PGJ(2) and DEX suppressed COX-2 promoter activity by interfering with the NF-kappaB signaling pathway. Transfection of a PPARgamma expression vector into the endothelial cells acquires this suppressive regulation of COX-2 gene by 15d-PGJ(2) but not by DEX. A selective COX-2 inhibitor, NS-398, inhibits production of PGD(2) in the U937 cells. Taking these findings together, we propose that expression of COX-2 is regulated by a negative feedback loop mediated through PPARgamma, 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.