Retinoic acid counteracts both the downregulation of thrombomodulin and the induction of tissue factor in cultured human endothelial cells exposed to tumor necrosis factor

Abstract

Inflammatory cytokines such as tumor necrosis factor-α (TNF-α) 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-α. The approximate 50% downregulation of TM antigen and cofactor activity induced by TNF-α (10 U/mL for 24 hours) was completely prevented when the cells were coincubated with both TNF-α and 10 μmol/L RA. In accordance with changes in cell surface TM antigen levels, the 70% decrease in TM messenger RNA (mRNA) induced by TNF-α was also prevented by 10 μmol/L RA. TNF-α induced TF activity of lysed cells (100-fold greater than untreated controls), an effect prevented when the cells were coincubated with both the TNF-α and 10 μmol/L RA. The 34-fold increase in TF mRNA levels induced by TNF-α (10 U/mL for 3 hours) was only two-fold in the presence of both TNF-α and RA. The effects of RA on the regulation of TM and TF expression in the cells exposed to TNF-α was dosedependent from 0.01 to 10 μmol/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-α. © 1992 by The American Society of Hematology.