INHIBITING INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR-ALPHA DOES NOT REDUCE INDUCTION OF PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 BY ENDOTOXIN IN RATS IN-VIVO

In experimental animals and humans, intravenous (IV) injection of endotoxin induces large increases in circulating plasminogen activator inhibitor type-1 (PAI-1), a major inhibitor of blood fibrinolysis. A similar increase is seen after the injection of interleukin-1 (IL-1) or of tumor necrosis factor-alpha (TNF-alpha), suggesting that these cytokines mediate the induction, by endotoxin, of PAI-1. To test this hypothesis we pretreated rats, before IV endotoxin, with compounds that inhibit the formation of cytokines (pentoxifylline; dexamethasone), or with compounds that inhibit the action of these cytokines (anti-TNF antiserum for TNF-alpha; IL-1 receptor antagonist for IL-1). None of these pretreatments affected the induction of PAI-1 synthesis by endotoxin. However, pretreatment did reduce the endotoxin-induced increase in plasma tPA antigen concentration. Thus, the data suggest that, in rats in vivo, TNF-alpha and IL-1 are not significantly involved in the induction of PAI-1 by endotoxin. (C) 1995 by The American Society of Hematology.