| Project/Area Number |
11838021
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Institution | NATIONAL CARDIOVASCULAR CENTER RESEARCH INSTITUTE |
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Principal Investigator |
INOUE Hiroyasu DEPT.OF PHARMACOLOGY, NATIONAL CARDIOVASCULAR CENTER RESEARCH INSTITUTE LABORATORY CHIEF, 薬理部, 室長 (40183743)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | CYCLOOXYGENASE / PROSTAGLANDIN / ENDOTHELIAL CELL / MACROPHAGE / PPARγ / NUCLEAR RECEPTOR / LIPOPOLYSACCHARIDE / GULUCOCORTICOID RECEPTOR / シクオロキシゲナーゼ / 内皮細胞 / 核内レセプター / 平滑筋細胞 |
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| 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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