|Budget Amount *help
¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 1992 : ¥300,000 (Direct Cost : ¥300,000)
Fiscal Year 1991 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Normal endothelial cells repress blood coagulation during generation of anticoagulant factors and are inhibiting formation of thrombosis. Thrombomodulin (TM) expressed on the surface of endothelial cells forms complex with thrombin and inhibits procoagulant activity of thrombin such as fibrin formation, platelet activation and activation of coagulation factors V and VIII. By the formation of complex, activity to activate protein C is further induced and production of thrombin is inhibited by activated protein C. Thus, TM modurates procoagulant activity of thrombin to anticoagulant activity and functions as anticoagulant. Although the above mentioned functions of TM were suggested from in vitro expeiments using purified TM, role and function of TM on the surface of endothelial cells had not been identified.
In the present studies, it was indicated that 1. TM expressed on the surface of endothelial cells also formed complex with thrombin and the complex activated protein C on the surface,
2. the cofactor activity of TM to activate protein C on the cell surface was about 10 times higher than that of purified TM. We demonstrated that TM expressed on surface of endothelial cells effectively functions as anticoagulant. It was further revealed that 3. when endothelial cells were exposed to tumor necrosis factor (TNF) or interleukin-1 (IL-1), transcriptional level and protein synthesis of TM was reduced and the cofactor activity to activate protein C on the cell surface was also decreased, 4. treatment of endothelial cells with retinoic acid (vitamin A acid) increased transcription level, protein synthesis and the cofactor activity of TM, and 5. retinoic acid returned to normal level of TM on the cells surface even when TM level was reduced by exposure of the cells to TNF. We proposed that one of causes of thrombosis generation in tumor or inflammation could be due to decrease in TM expression by exposure to the cytokines, and suggested possibility of therapy by retinoic acid on thrombosis in the case of above deseases. Less