TUMOR-NECROSIS-FACTOR, ITS RECEPTORS AND THE CONNECTION WITH INTERLEUKIN-1 AND INTERLEUKIN-6

Cytokines are important mediators of the effects observed after the ad ministration of endotoxin. One of them, tumor necrosis factor, is part icularly important since it plays a cardinal role in two major endotox in activities: its antitumor effect and its capacity to induce a syste mic inflammatory response syndrome. TNF exerts its activity on a wide variety of target cells by the triggering of two distinct receptor typ es. TNF-R55 and TNF-R75. They induce distinct intracellular signals bu t can have cooperative effects. So, their differential triggering or m odulation may have clinically relevant consequences. Based upon observ ations in the mouse, where hTNF does not interact with the INF-R75 whi le mTNF triggers both receptor types, we propose that both receptors n eed to be triggered to obtain lethality after the administration of TN F. Since human TNF has retained antitumor activity, esp. in combinatio n with IFN-gamma, TNF-mutants that are selective agonists for the TNF- R55 might have a broader therapeutic margin. One such human TNF mutant was already shown to be as effective as the wild-type hTNF in a xenog raft model. However, several sensitizing agents may mimic TNF-R75 trig gering and so make TNF-R55 triggering a lethal challenge. The fact tha t two such agents, RU38486 and IL-1 have similar effects regarding the ir kinetics and their capacity to sensitize for the lethality- and IL- 6-inducing effect of hTNF may give a hint regarding the mechanism of t he sensitizing effect.