PENTOXIFYLLINE PREVENTS TUMOR NECROSIS FACTOR-INDUCED SUPPRESSION OF ENDOTHELIAL-CELL SURFACE THROMBOMODULIN

Thrombomodulin (TM) expression has been reported to be down-regulated by cytokines (endotoxin, interleukin-1 , and tumor necrosis factor). We report, in the present study, up-regulation of surface TM antigen of human umbilical vein endothelial cells (HUVECs) by pentoxifylline (PTX) which is one of the agents that can increase intracellular cyclic AMP in HUVECs at therapeutic concentrations. Surface TM antigen was measured by an enzyme immunoassay. PTX increased surface TM antigen and intracellular cAMP in HUVECs in a dose dependent manner. Up-regulation of TM by PTX was due to de novo synthesis of TM protein resulting from increased TM mRNA levels. PTX counterbalanced the TNF-induced suppression of TM expression. These results suggest that protein kinase A may be involved in cellular regulatory mechanism for TM expression and PTX may protect partially against TNF-induced endothelial cell injury and restore anticoagulant state of endothelium.