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Studies on Regulation of Thrombomodulin on Expression in Cells Treated with Retinoic Acid

视黄酸处理细胞中血栓调节蛋白表达调控的研究

基本信息

批准号：
03671064
负责人：
HORIE Shuichi
金额：
$ 1.34万
依托单位：
Teikyo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1993
项目状态：
已结题

项目摘要

Thrombomodulin(TM) is a surface glycoprotein on endothelial cells, and represents one of the most valuable regulatory factors in the anticoagulant system. The present study was investigated the effect of retinoic acid (RA) on the expression of TM and its regulatory mechanism in endothelial cells and in HL-60 cells during its differentiation. Results indicated that RA caused to the increase in TM mRNA level to up-regulate TM expression, and suggested that RA-induced up-regulation of TM on endothelial cells was independent of cyclic AMP level. We found that RA effectively counteracts the inflammatory cytokines-induced prothrombotic properties of endothelial cells, caused by downregulating TM and inducing tissue factor expression. Thus, RA may be considered for evaluation not only as an antileukemic, but also as an antithrombotic drug. On the other hand, trace amounts of TM antigen were induced in neutrophilic cells differentiated from HL-60 by treatment with RA and found that different levels of TM were induced in monocytic, macrophagic and neutrophilic cells differentiated from HL-60 cells. From the study of the promoter activity of TM it was suggested that RA-dependent increase in TM transcription in cells was associated with the nucleotide sequence located in the 5'-flanking region of the TM gene. Alternatively, it is considered that the regulatory mechanism of TM expression in cells treated with RA is dependent on the amount of functional RA receptor protein in each cell.

血栓调节蛋白（Thrombomodulin， TM）是内皮细胞表面的一种糖蛋白，是抗凝系统中最有价值的调节因子之一。本研究旨在探讨维甲酸（RA）对内皮细胞和HL-60细胞分化过程中TM表达的影响及其调控机制。结果表明，RA可引起TM mRNA水平升高，上调TM表达，RA诱导的TM对内皮细胞的上调与环AMP水平无关。我们发现RA通过下调TM和诱导组织因子表达，有效地抵消炎症细胞因子诱导的内皮细胞的血栓形成特性。因此，类风湿关节炎不仅可以作为抗白血病药物，还可以作为抗血栓药物进行评估。另一方面，在HL-60细胞分化的嗜中性细胞中，RA诱导了微量TM抗原，发现HL-60细胞分化的单核细胞、巨噬细胞和嗜中性细胞均诱导了不同水平的TM。对TM启动子活性的研究表明，细胞中TM转录的ra依赖性增加与TM基因5'侧区的核苷酸序列有关。另一种观点认为，在RA处理的细胞中，TM表达的调控机制取决于每个细胞中功能性RA受体蛋白的数量。