Role of tumour necrosis factor in the enhanced sensitivity of mice to endotoxin after exposure to lead

Abstract

Heavy metals administered to animals, at doses which appear relatively innoxious by themselves, enhance susceptibility to endotoxin. The mechanisms which underly this phenomenon are not yet fully understood. In this study we investigated the role of the cytokine Tumour Necrosis Factor (TNF), an important mediator of the effects of endotoxin, in this phenomenon. First it was studied whether lead enhances sensitivity of mice to endotoxin and to TNF. Lead appeared to enhance sensitivity to both endotoxin and TNF resulting in mortality of mice at low endotoxin and TNF doses. Next we studied the influence of lead on serum TNF levels after stimulation by endotoxin. Lead treated mice showed lower TNF blood levels two hours after injection of endotoxin and lead. Six and eight hours after injection TNF levels of lead treated mice were higher compared to those of mice injected with endotoxin only. In the last part of our investigation, we studied the influence of a monoclonal hamster anti TNF antibody on the effect of combined lead-endotoxin exposure. Administration of the antibody prevents lethality completely. Our data indicate that TNF plays a central role in the phenomenon of the enhanced susceptibility of animals to endotoxin after exposure to lead. The enhanced susceptibility to endotoxin is caused by an enhanced susceptibility to TNF and possibly by a prolonged exposure to a higher level of TNF.