Endothelium is a target tissue for tumor necrosis factor

Tumor necrosis factor/cachectin (TNF) is a mediator of the septic state, which involves diffuse abnormalities of coagulation throughout the vasculature. Since previous studies have demonstrated that endothelial cells can play an active role in coagulation, they examined if TNF could modulate endothelial cell hemostatic properties. Incubation of purified recombinant TNF with cultured endothelial cells resulted in time and dose-dependent acquisition of tissue factor procoagulant activity. Concomitant with enhanced procoagulant activity, TNF also suppressed endothelial cell cofactor activity for the anticoagulant protein C pathway; both thrombin-mediated protein C activation and formation of functional activated protein C-protein S complex on the cell surface were considerably attenuated. Thus, TNF induced a unidirectional shift in cell surface hemostatic properties favoring promotion of clot formation. This led us to carry out binding studies with 125I-TNF. TNF bound to monolayers in a saturable manner with half-maximal binding at 120pM. Interaction of TNF with the endothelium led to synthesis and elaboration of interleukin-1 (IL-1). IL-1 generation was half-maximal at a TNF concentration of ∼ 150pM. These data indicate that IL-1 can bind to endothelium resulting in modulation of its hemostatic properties and elaboration of IL-1. Endothelium can thus play an integral role in the host response to neoplastic and inflammatory stimuli