Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1.

Abstract

Human recombinant tumor necrosis factor (rTNF) was found to act directly on cultured human vascular endothelium to induce a tissue factor-like procoagulant activity (PCA). After a 4-hr incubation in rTNF (100 units/ml), serially passaged endothelial cells isolated from umbilical veins, saphenous veins, iliac arteries, and thoracic aortae demonstrated a dramatic increase (4-to 15-fold, 21 experiments) in total cellular PCA as measured with a one-stage clotting assay. rTNF-induced PCA was also expressed at the surface of intact viable endothelial monolayers. Induction of PCA by rTNF was concentration dependent (maximum, 500 units/ml), time dependent, reversible, and blocked by cycloheximide and actinomycin D, and it occurred without detectable endothelial cell damage. Actions of rTNF were compared with those of natural human interleukin 1 (IL-1) derived from stimulated monocytes and two distinct species of recombinant IL-1, each of which also induced endothelial PCA. The use of recombinant polypeptides and specific neutralizing antisera established the distinct natures of the mediators. The minetics ofthe endothelial PCA responses to TNF and IL-1 werf similar, demonstrating a rapid rise to peak activity at -4 hr, apd a decline toward basal levels by 24 hr. This characteristic decline in PCA after prolonged incubation with TNF or IL-1 was accompanied by selective endothelial hyporesponsiveness to the initially stimulating monokine. Interestingly, the effects of TNF and IL-1 were found to be additive even at apparent maximal doses of the individual monokines. Endothelial-directed actions of TNF, alone or in combination with other monokines, may be important in the initiation ofcoagulation and inflammatory responses in vivo.

Vitamin D3 down‐regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen‐associated molecular patterns

“…LPS-induced expression of TF (CD142) in activated monocytes triggers thrombosis and may culminate in disseminated intravascular coagulation (DIC) [12]. Moreover, TNF-a per se is known to be a potent inducer of TF expression [13]. The occurrence of DIC as a secondary complication of sepsis with gram-negative bacteria is associated with poor prognosis and is an independent predictor of mortality [14].…”

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

“…Inflammatory mechanisms upregulate procoagulant factors, downregulate natural anticoagulants and inhibit fibrinolytic activity [2]. Endotoxin, tumor necrosis factor alpha (TNF-a) and interleukin-1a induce tissue factor (TF) expression, primarily on endothelial cells and monocytes/macrophages, promoting blood coagulation [3]. Activation of the complement C5b-C9 complex changes the cell surface to a more procoagulant phenotype by the shift of negatively charged phospholipids from the inner to the outer membrane [4].…”

Induction by Toxic-Shock-Syndrome Toxin-1 of a Circulating Tumor Necrosis Factor-Like Substance in Rabbits and of Immunoreactive Tumor Necrosis Factor and Interleukin-1 from Human Mononuclear Cells

“…TNF is an endogenous pyrogen [9], and TNF shares with IL-1 many biologic functions. Recombinant IL-1 and TNF increase hepatic acute-phase protein synthesis [10], decrease hepatic albumin synthesis [10,11], in duce synovial collagenase and prostaglandin E2 [12], cause release of procoagulant activity from vascu lar endothelium [13], and inhibit lipoprotein lipase synthesis [14,15]. We recently demonstrated that in jection of recombinant human IL-1 (3 or recombinant human TNF decreases systemic arterial pressure in the rabbit and that combined administration of IL-1 and TNF is more potent than either cytokine alone in induction of a shock-like state [16].…”