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

血栓调节蛋白（TM）是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。本研究探讨了维甲酸（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通过增加TM mRNA水平，上调TM表达，并提示RA上调内皮细胞TM表达与cAMP水平无关。我们发现，RA有效地抵消了炎症细胞因子诱导的内皮细胞血栓形成的特性，所造成的下调TM和诱导组织因子的表达。因此，RA不仅可以作为抗白血病药物，而且可以作为抗血栓药物进行评价。另一方面，微量的TM抗原诱导HL-60细胞分化的嗜酸性细胞与RA的处理，并发现不同水平的TM诱导单核细胞，巨噬细胞和HL-60细胞分化的嗜酸性细胞。从TM启动子活性的研究表明，RA依赖的TM转录在细胞中的增加与位于TM基因5 '侧翼区的核苷酸序列有关。或者，认为用RA处理的细胞中TM表达的调节机制取决于每个细胞中功能性RA受体蛋白的量。

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.