We have previously studied the effects of recombinant soluble type I IL-1 receptor in human subjects challenged with intravenous endotoxin (92-CC 0141). This product neutralized circulating IL-1 yet also neutralized the effects of IL-1 receptor antagonist in a dose-related fashion. The soluble receptor was developed as an anti-inflammatory agent. It resulted, however, in a net proinflammatory cytokine response with enhanced levels of intracellular IL-1beta, and increased levels of tumor necrosis factor (TNF) and IL-8 after endotoxin administration. We have previously shown that endotoxin is a potent initiator of the contact system of kinin and kallikrein generation, and that the timing of its activation is altered by inhibiting TNF, another proinflammatory cytokine. We are currently evaluating the effects of IL-1 inhibition on activation of the kinin-kallikrein system. Functional and antigenic assays for prekallikrein, C1 inhibitor activity, Factor II, Factor V, cysteine protease inhibitor activity, as well as markers of the activation of fibrinolysis and coagulation will be performed.
