TUMOR-NECROSIS-FACTOR-ALPHA INDUCES ACTIVATION OF COAGULATION AND FIBRINOLYSIS IN BABOONS THROUGH AN EXCLUSIVE EFFECT ON THE P55 RECEPTOR

Tumor necrosis factor-alpha (TNF-alpha) can bind to two distinct trans membrane receptors, the p55 and p75 TNF receptors. We compared the cap ability of two mutant TNF proteins with exclusive affinity for the p55 or p75 TNF receptor with that of wild type TNF, to activate the hemos tatic mechanism in baboons. Both activation of the coagulation system, monitored by the plasma levels of thrombin-antithrombin III complexes , and activation of the fibrinolytic system (plasma levels of tissue-t ype plasminogen activator, and plasminogen activator inhibitor type I) , were of similar magnitude after intravenous injection of wild type T NF or the TNF mutant with affinity only for the p55 receptor. Likewise , wild type TNF and the TNF p55 specific mutant were equally potent in inducing neutrophil degranulation (plasma levels of elastase-alpha(1) -antitrypsin complexes). Wild type TNF tended to be a more potent indu cer of secretory phospholipase A(2) release than the p55 specific TNF mutant. Administration of the TNF mutant binding only to the p75 recep tor did not induce any of these responses. We conclude that TNF-induce d stimulation of coagulation, fibrinolysis, neutrophil degranulation, and release of secretory phospholipase A(2) are predominantly mediated by the p55 TNF receptor. (C) 1996 by The American Society of Hematolo gy.