CYTOKINE-INDUCED PROCOAGULANT ACTIVITY IN MONOCYTES AND ENDOTHELIAL CELLS FURTHER ENHANCEMENT BY CYCLOSPORINE

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Abstract
IL-1, IL-2, and TNF.alpha. are important biological response modifiers of inflammatory and immunological reactions. Our experiments show that these cytokines are potent inducers of thromboplastin (TPL) activity but that their effects differ with regard to cell type and kinetics in human umbilical vein endothelial cells (HUVEC), monocytes (M), and mononuclear blood cells (MNC). Recombinant IL-1.alpha., rIL-1.beta. and rTNF.alpha. all induced a dose-dependent increase in endothelial cell TPL activity, whereas rIL-2 had essentially no such effect. In the case of M and MNC cultures, IL-1 and IL-2 each induced TPL synthesis, IL-2 somewhat more slowly than IL-1. Special care was taken to exclude the effect of endotoxin present in the IL-1 preparations. Recombinant TNF.alpha. had a markedly smaller or no effect. When LPS was used to induce TPL synthesis, addition of rTNF.alpha. further enhanced HUVEC TPL, whereas no effect or a decrease in TPL was seen in MNC and M, especially in the presence of CsA and TNF.alpha.. Recombinant IL-1.beta. also induced the synthesis of clotting factor VII in monocytes, thus allowing the formation of TPL-factor VII complexes, a most powerful trigger of blood clotting. IL-1.alpha., IL-2, and TNF.alpha. had no effect on the level of factor VII activity. Cyclosporine significantly augmented the level of TPL activity in HUVEC stimulated with rIL-1.alpha., rIL-1.beta., and rTNF.alpha. and in MNC and M stimulated with rIL-1.alpha., rIL-1.beta., and rIL-2. These actions of cytokines and cyclosporine may contribute significantly to the development of thrombotic reactions and fibrin deposits in transplanted organs, as well as to other pathophysiological pathways where activated clotting factors are involved.