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

血栓调节蛋白(TM)是一种内皮细胞表面糖蛋白，是抗凝系统中最有价值的调节因子之一。本研究探讨维甲酸(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基因表达水平升高，从而上调TM的表达，提示RA诱导内皮细胞TM表达上调不依赖于cAMP水平。我们发现，RA有效地对抗炎性细胞因子诱导的内皮细胞血栓前特性，这种特性是通过下调TM和诱导组织因子表达而引起的。因此，RA不仅可以作为一种抗白血病药物，还可以作为一种抗血栓药物进行评估。另一方面，用RA诱导HL-60分化的中性粒细胞表达微量TM抗原，发现从HL-60分化的单核细胞、巨噬细胞和中性粒细胞均能诱导出不同程度的TM抗原。对TM启动子活性的研究表明，细胞中TM转录水平的增加与TM基因5‘侧翼区的核苷酸序列有关。另一种观点认为，维甲酸处理细胞中TM表达的调节机制依赖于每个细胞中功能维甲酸受体蛋白的数量。

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.