Species specificity and involvement of other cytokines in endotoxic shock action of recombinant tumour necrosis factor in mice

Abstract

We compared the effects of human rTNF and murine rTNF in murine models of toxicity, esp. the induction of endotoxic shock. As was the case for the antitumour activity, we found a marked difference in activity between these two TNFs. Only murine rTNF was able to cause lethality, while human rTNF needed the synergistic action of sensitizing agents to become lethal. Further experiments, such as the study of IL-6 induction by TNF in mice, allowed us to distinguish two types of TNF effects: those that can equally well be exerted by human rTNF and by murine rTNF (type I effects) and those that can only be exerted by murine rTNF (type II effects). Both types of effects, the "toxic" (a type I effect) and the sensitizing (a type II effect) are needed to produce a lethal outcome. Other cytokines such as IL-1 and IFN-gamma, however, can also exert such a sensitizing effect and consequently lead to a fatal outcome when co-administered with human rTNF.