Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells.

Abstract

Tumor necrosis factor (TNF) dramatically alters the levels of various surface components of the blood vessel wall, such as blood coagulation enzyme receptors, leukocyte-adhesive receptors, and class 1 major histocompatibility complex antigens, which may have relevance to its effects in septic shock, angiogenesis, and tumor growth. However, the precise mechanism by which the cytokine is able to accomplish this remodeling of the endothelial cell surface has not been defined. We have demonstrated that exposure of bovine and human endothelial cells to TNF leads to suppression of the functional cell surface thrombin receptor, thrombomodulin (TM), and TM mRNA of virtually identical magnitude. The cytokine has no significant effect on the stability of TM mRNA or endothelial receptor turnover. Nuclear run-on studies reveal that the treatment of endothelial cells with TNF for short periods reduces TM gene transcription to as little as 3% of control values and that this inhibition does not require new protein synthesis.

Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties.

“…The effects of AGE-BSA on these endothelial coagulant properties were slower in their onset and more sustained, compared with the more rapid effects of cytokines such as TNF (4,7,14,19,35,38). Furthermore, in contrast to TNF, which decreases total thrombomodulin antigen in parallel with the fall in cell surface thrombomodulin activity (14,19,35), AGE-BSA did not depress the pool of total thrombomodulin antigen, but rather exerted its effect more selectively on accessibility of the cell surface receptor. Induction of tissue factor in response to AGE-BSA was also quite different than the response to cytokines, such as TNF or IL-1 (4,7,38,45).…”

The cytokine‐mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia

“…Protein C is an important inhibitor of factor Va and factor VIIIa and is activated by complex formation of thrombin with an endothelial cell surface protein, thrombomodulin (TM). The anticoagulant capacity of protein C is enhanced by its natural co-factor, protein S. The downregulation of thrombomodulin during sepsis, which is probably caused by cytokines [in particular tumour necrosis factor (TNF)], results in diminished protein C activity and may enhance the procoagulant state [23,24]. It has indeed been shown that treatment with (activated) protein C concentrate can reduce the coagulopathy in bacteraemic baboons [25].…”

Increased level of tumor necrosis factor-α in patients with antiphospholipid syndrome: marker not only of inflammation but also of the prothrombotic state

“…CRP itself increases TF and decreases TF pathway inhibitor (TFPI) concentrations, what may be important in pathogenesis of arterial thrombosis and myocardial infarction [5]. Of the natural anticoagulants, protein C pathway appears to be the most strongly influenced by inflammation with thrombomodulin (TM) and the endothelial cell protein C receptor (EPCR) being both downregulated by TNF-a [6].…”