Endotoxin tolerance is associated with reduced secretion of tumor necrosis factor

Bacterial endotoxin effects are partially mediated by tumor necrosis factor (TNF). It is known that sublethal doses of endotoxin induce transient refractoriness (tolerance) to some of its effects. We studied the role of TNF in endotoxin tolerance in rats. Weight loss, lethality, and TNF production were measured after an initial dose of endotoxin and after subsequent doses. Weight loss reached its peak 72 hours after the initial endotoxin challenge, followed by recovery even under continued administration of endotoxin. While tolerant, rats could survive a dose of endotoxin that was lethal for 100% of naive rats. The high serum levels of TNF, observed 90 minutes after the first dose of endotoxin, markedly diminished when rechallenged during tolerance. Recovery of responsiveness to these effects followed the refractory phase by 3 weeks. We concluded that endotoxin tolerance is associated with a reduced secretion of TNF.