核内受容体Peroxisome Proliferator-Activated Receptorを介する誘導型シクロオキシゲナーゼの発現調節に関する研究

概要

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Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandins (PG) synthesis, 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 proliferatoractivated receptor-γ (PPARγ). 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. PPARγmRNA expressed abundantly in the U937 cells is down-regulated by LPS. In contrast, LPS up-regulates mRNA for the glucocorticoid receptor, and its ligand dexamethasone (DEX) strongly suppresses the LPS-induced expression of COX-2 gene. Transfection of a PPARy-expression vector into the endothelial cells acquires this suppressive regulation of COX-2 gene transcription by 15d-PGJ_2, but not by DEX. 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 attribute to various expression patterns and physiological functions of COX-2.
日本ビタミン学会の論文
2003-08-25