Impaired activation of nuclear factor-kappaB in endotoxin-tolerant rats is associated with down-regulation of chemokine gene expression and inhibition of neutrophilic lung inflammation.

We postulated that repeated injections of endotoxin could induce a state of endotoxin tolerance in rats that is mediated at least partially through a nuclear factor (NF)-kappaB-dependent mechanism. We treated rats with four doses of endotoxin (0.06 or 0.6 mg/kg/day) and evaluated the ability of these treatments to modulate activation of the transcription factor NF-kappaB induced by treatment with high dose endotoxin (6 mg/kg). In lung tissue, NF-kappaB activation in response to i.p. injection of high dose endotoxin was blocked by treatment with four daily doses of endotoxin at 0.6 mg/kg/day. Endotoxin tolerance in rats was associated with diminished endotoxin-induced mRNA expression of the NF-kappaB-dependent rat chemokine, cytokine-induced neutrophil chemoattractant. Treatment of rats with four daily doses of 0.6 mg/kg/day of endotoxin almost completely abolished the neutrophilic alveolitis that occurs in rats following i.p. injection of high dose endotoxin. These data indicate that in vivo tolerance to endotoxin challenge is associated with and possibly mediated by inhibition of NF-kappaB activation. Potentially, endotoxin tolerance could be exploited to limit inflammation in disease states whose pathobiology is related to excessive or unregulated inflammation.