Induction of endotoxin tolerance depletes nuclear factor-kappa B and suppresses its activation in rat alveolar macrophages

To investigate the mechanism of endotoxin tolerance in macrophages, a rat alveolar macrophage cell line (NR8383) was rendered endotoxin tolerant by treatment with endotoxin at 40 ng/mL for 48 h, This treatment induced a state of tolerance such that subsequent exposure to high-dose endotoxin (5 mu g/mL) resulted in decreased production of macrophage inflammatory protein-2, tumor necrosis factor alpha, and nitric oxide compared to endotoxin-sensitive cells, Suppressed mediator production by endotoxin-tolerant cells was associated with impaired activation of nuclear factor-kappa B (NF-kappa B) in response to treatment with 5 mu g/mL of endotoxin, This impairment of NF-kappa B activation was found to be associated with depletion of latent NF-kappa B (both RelA and p50) in the cytoplasm of endotoxin-tolerant cells, These data suggest that a mechanism of endotoxin tolerance is depletion of RelA/p50, which could limit the amount of NF-kappa B available for activation by subsequent stimuli and thereby inhibit transcription of NF-kappa B-dependent genes, Limiting NF-kappa B-dependent inflammatory gene transcription by inducing endotoxin tolerance is a potential therapeutic strategy for diseases where excessive production of inflammatory mediators leads to tissue injury.