RECOMBINANT IL-1 RECEPTOR ANTAGONIST PROTECTS AGAINST TNF-INDUCED LETHALITY IN MICE

The possible role of induced IL-l in a number of in vivo actions of TN F was investigated. We were particularly interested to know whether a species-specific induction of IL-1 might explain the important differe nces observed between murine TNF and human TNF in systems such as leth al shock and the induction of long lasting, high levels of circulating IL-6 in mice. We also studied the possible involvement of IL-1 in the sensitization to TNF observed in tumor-bearing mice or in combination with D(+)-galactosamine or RU38486, particularly because such sensiti zation results in the loss of species-specific differences between bot h TNF. Using a specific rlL-1R antagonist (IL-1ra), which inhibits the binding of IL-1 to the IL-1R type I, we were able to protect mice aga inst a lethal murine TNF injection. However, the induction of high lev els of circulating IL-6 by murine TNF was not affected, although IL-1r a almost completely blocked the induction of IL-6 by exogenously admin istered IL-1l. Furthermore, the increased susceptibility of tumor-bear ing mice to human TNF, relative to control mice, or the sensitization by co-administration of RU38486 or D(+)-galactosamine do not seem to b e mediated by IL-1.