Ishii H, Horie S, Kizaki K, Kazama M
Department of Clinical Biochemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan.
Blood. 1992 Nov 15;80(10):2556-62.
Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) shift the hemostatic balance of endothelial cell surfaces in favor of prothrombotic properties by downregulating thrombomodulin (TM) and inducing tissue factor (TF) expression. We investigated the effects of retinoic acid (RA) on the prothrombotic properties of cultured umbilical vein endothelial cells exposed to TNF-alpha. The approximate 50% downregulation of TM antigen and cofactor activity induced by TNF-alpha (10 U/mL for 24 hours) was completely prevented when the cells were coincubated with both TNF-alpha and 10 mumol/L RA. In accordance with changes in cell surface TM antigen levels, the 70% decrease in TM messenger RNA (mRNA) induced by TNF-alpha was also prevented by 10 mumol/L RA. TNF-alpha induced TF activity of lysed cells (100-fold greater than untreated controls), an effect prevented when the cells were coincubated with both the TNF-alpha and 10 mumol/L RA. The 34-fold increase in TF mRNA levels induced by TNF-alpha (10 U/mL for 3 hours) was only two-fold in the presence of both TNF-alpha and RA. The effects of RA on the regulation of TM and TF expression in the cells exposed to TNF-alpha was dose-dependent from 0.01 to 10 mumol/L RA. The present results suggest that RA may affect on the mRNA level to alter TM and TF expression, effectively counteracting expression of prothrombotic properties of endothelial cells induced by inflammatory cytokines such as TNF-alpha.
诸如肿瘤坏死因子-α（TNF-α）等炎性细胞因子通过下调血栓调节蛋白（TM）并诱导组织因子（TF）表达，使内皮细胞表面的止血平衡向促血栓形成特性倾斜。我们研究了视黄酸（RA）对暴露于TNF-α的培养脐静脉内皮细胞促血栓形成特性的影响。当细胞与TNF-α（10 U/mL，作用24小时）和10 μmol/L RA共同孵育时，TNF-α诱导的TM抗原和辅因子活性约50%的下调被完全阻止。与细胞表面TM抗原水平的变化一致，10 μmol/L RA也阻止了TNF-α诱导的TM信使核糖核酸（mRNA）70%的减少。TNF-α诱导裂解细胞的TF活性（比未处理对照高100倍），当细胞与TNF-α和10 μmol/L RA共同孵育时，这种作用被阻止。TNF-α（10 U/mL，作用3小时）诱导的TF mRNA水平34倍的增加，在同时存在TNF-α和RA时仅为2倍。RA对暴露于TNF-α的细胞中TM和TF表达调节的影响在0.01至10 μmol/L RA范围内呈剂量依赖性。目前的结果表明，RA可能在mRNA水平上影响TM和TF的表达，有效对抗诸如TNF-α等炎性细胞因子诱导的内皮细胞促血栓形成特性的表达。
