| Research Abstract |
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-Δ^<12,14>PGJ_2(15d-PGJ_2) 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-PGJ_2 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 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 gene although both 15d-PGJ_2 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-PGJ_2 but not by DEX.A selective COX-2 inhibitor NS-398 inhibits production of PGD_2 in the U937 cells. Taken together, we propose that expression of COX-2 will be 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.
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