TAILIEUCHUNG - Báo cáo khoa học: Liver X receptor agonists inhibit tissue factor expression in macrophages

Exposure of blood to tissue factor (TF) rapidly initiates the coagulation serine protease cascades. TF is expressed by macrophages and other types of cell within atherosclerotic lesions and plays an important role in throm-bus formation after plaque rupture. Macrophage TF expression is induced by pro-inflammatory stimuli including lipopolysaccharide (LPS), inter-leukin-1band tumor necrosis factor-a. Here we demonstrate that activation of liver X receptors (LXRs) LXRaand LXRbsuppresses TF expression | iFEBS Journal Liver X receptor agonists inhibit tissue factor expression in macrophages Naoki Terasaka1 Ayano Hiroshima1 Akiko Ariga1 Shoko Honzumi1 Tadashi Koieyama1 Toshimori Inaba2 and Toshihiko Fujiwara1 1 Pharmacology and Molecular Biology Research Laboratories Sankyo Co. Ltd Tokyo Japan 2 Pharmacodynamics Research Laboratories Sankyo Co. Ltd Tokyo Japan Keywords atherosclerosis genes lipopolysaccharide liver X receptor macrophage tissue factor Correspondence N. Terasaka Pharmacology and Molecular Biology Research Laboratories Sankyo Co. Ltd 1-2-58 Hiromachi Shinagawa-ku Tokyo 140-8710 Japan Fax 81 3 5436 8566 Tel 81 3 3492 3131 E-mail terasa@ Received 5 November 2004 revised 17 January 2005 accepted 4 February 2005 doi Exposure of blood to tissue factor TF rapidly initiates the coagulation serine protease cascades. TF is expressed by macrophages and other types of cell within atherosclerotic lesions and plays an important role in thrombus formation after plaque rupture. Macrophage TF expression is induced by pro-inflammatory stimuli including lipopolysaccharide LPS interleukin-1 b and tumor necrosis factor-a. Here we demonstrate that activation of liver X receptors LXRs LXRa and LXRb suppresses TF expression. Treatment of mouse peritoneal macrophages with synthetic LXR agonist T0901317 or GW3965 reduced TF expression induced by pro-inflammatory stimuli. LXR agonists also suppressed TF expression and its activity in human monocytes. Human and mouse TF promoters contain binding sites for the transcription factors AP-1 NFkB Egr-1 and Sp1 but no LXR-binding sites could be found. Cotransfection assays with LXR and TF promoter constructs in RAW cells revealed that LXR agonists suppressed LPS-induced TF promoter activity. Analysis of TF promoter also showed that inhibition of TF promoter activity by LXR was at least in part through inhibition of the NFkB signaling pathway. In addition in vivo LXR agonists .

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