Lehmann V, Freudenberg M A, Galanos C
J Exp Med. 1987 Mar 1;165(3):657-63. doi: 10.1084/jem.165.3.657.
The toxic properties of human recombinant tumor necrosis factor (TNF) were investigated in mice made hypersensitive to endotoxin by treatment with D-galactosamine. C3H/TifF mice treated with D-galactosamine were rendered sensitive to the lethal effects of submicrogram amounts of TNF. In the absence of D-galactosamine, TNF caused approximately 80% lethality with 500 micrograms. The duration of sensitization to TNF lasted up to 8 h after D-galactosamine administration, that towards LPS, up to 4 h. As with LPS, with TNF sensitization could be inhibited by uridine administered up to 2 h after D-galactosamine/TNF, showing that the early biochemical alterations in the liver known to be necessary for sensitization to LPS are also necessary for sensitization to TNF. In contrast to LPS, the toxicity of TNF was expressed also in D-galactosamine-treated endotoxin-resistant C3H/HeJ mice. The susceptibility of these mice to TNF was identical to that of endotoxin sensitive mice. In the absence of D-galactosamine the toxicity of TNF in C3H/HeJ mice was comparable to that obtained in C3H/TifF mice, being lethal with amounts of the order of 500 micrograms. The present results support the hypothesis that TNF is a mediator of lethal toxicity of endotoxin.
通过用D-半乳糖胺处理使小鼠对内毒素过敏，在此基础上研究了人重组肿瘤坏死因子（TNF）的毒性特性。用D-半乳糖胺处理的C3H/TifF小鼠对亚微克量的TNF的致死作用变得敏感。在没有D-半乳糖胺的情况下，500微克TNF可导致约80%的致死率。对TNF的致敏持续时间在给予D-半乳糖胺后长达8小时，对LPS的致敏持续时间长达4小时。与LPS一样，在给予D-半乳糖胺/TNF后2小时内给予尿苷可抑制对TNF的致敏，这表明已知对LPS致敏所必需的肝脏早期生化改变对TNF致敏也是必需的。与LPS不同，TNF的毒性在经D-半乳糖胺处理的内毒素抗性C3H/HeJ小鼠中也有表现。这些小鼠对TNF的敏感性与内毒素敏感小鼠相同。在没有D-半乳糖胺的情况下，C3H/HeJ小鼠中TNF的毒性与在C3H/TifF小鼠中获得的毒性相当，500微克左右的量即可致死。目前的结果支持TNF是内毒素致死毒性介质的假说。
