Transforming Growth Factor Betal and Beta2 Induce Down-Modulation of Thrombomodulin in Human Umbilical Vein Endothelial Cells

Abstract

SummaryTo investigate the effects of transforming growth factor-betas (TGF-βs) on endothelial anticoagulant activity, we assayed thrombomodulin (TM) activity and antigen levels of human umbilical vein endothelial cells (HUVECs) incubated with TGF-βs in vitro. TGF-β1 suppressed surface TM activity and surface TM antigen levels maximally 12 h after incubation in dose-dependent manners. TGF-β2 was almost equipotent with TGF-β1 for the suppression of them. Both TGF-βs suppressed total TM antigen level in HUVECs, and the time course of the suppression was similar to that of the cell surface TM antigen level. The maximal reductions of TM mRNA levels by TGF-βs were observed at several hours ahead of those observed in both surface and total TM antigen levels, suggesting that the TGF-β-mediated suppression of TM antigen of HUVECs is primarily regulated at the TM mRNA level. Our present work suggests that the down-modulation of TM level induced by TGF-βs in HUVECs contributes in vivo to promoting the thrombogenesis either at the sites of injury of vessel walls, such as atherosclerotic lesions where TGF-β1 is released from platelets, smooth muscle cells and monocytes, or at neovascular walls in tumors secreting TGF-β2.

Thrombomodulin expression in colorectal carcinoma is protective and correlates with survival

“…Expression is affected by a range of pathophysiological stimuli (Maruyama et al, 1985;Dittman et al, 1989;Ohji et al, 1995;Calnek and Grinnell, 1998;Ishii et al, 2003;Shi et al, 2003) and the effect of a specific stimulus varies with the cell type involved (Grey et al, 1998).…”

Inactivation of Thrombomodulin by Ionizing Radiation in a Cell-Free System: Possible Implications for Radiation Responses in Vascular Endothelium

“…In the post-radiation situation, TM expression is downregulated by inflammatory cytokines such as TNFα, IL1, or IL6, NFkB (6,(8)(9)(10), or by exposure to lipopolysaccharide or endotoxin (19). TM may also be shed into the blood stream by being cleaved from the endothelial plasma membrane by ectodomain shedding (12,20).…”

“…First, many cytokines that are upregulated during the radiation response, such as interleukin 1 (IL1), tumor necrosis factor α (TNFα), and transforming growth factor β (TGFβ) reduce TM expression at the transcriptional level (6)(7)(8)(9). The transcription factor nuclear factorκB (NFκB), which is activated by radiation as well as in response to cytokines that are released in increased amounts during inflammation, may also be involved in the regulation of TM (10).…”

Recombinant adeno-associated virus vector-transduced vascular endothelial cells express the thrombomodulin transgene under the regulation of enhanced plasminogen activator inhibitor-1 promoter

“…Monoclonal antibodies used in ELISA or immunohistochemistry did not react with bovine TM, thus the TM molecule detected by ELISA in BCEs infected with rAAV2 vectors was recombinant human TM. Transduction of BCEs was dose-dependent up to MOI of 10 6 and was time-dependent, reaching a plateau after 16 h incubation of BCEs with rAAV2 vectors (Figure 3). These data were comparable with previous data.…”

“…2 TM gene expression is down-regulated by inflammatory cytokines, bacterial endotoxins, 1,[3][4][5] 1690-1697. β1 (TGFβ1). 6 In particular, inflammatory cytokines and endotoxins induce expression of procoagulant tissue factor in endothelial cells and monocytes/macrophages, and down-regulate TM gene expression in endothelial cells resulting in a thrombotic state. 1 Plasminogen activator inhibitor 1 (PAI-1), the physiological inhibitor of both tissue-type plasminogen activator and urokinase-type plasminogen activator, is secreted from vascular endothelial cells and plays a role as a primary regulator of vascular thromobolysis.…”