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

Blackwell TS, Blackwell TR, Christman JW
J Leukoc Biol. 1997 62 (6): 885-91

PMID: 9400831 · DOI:10.1002/jlb.62.6.885

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 microg/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-kappaB (NF-kappaB) in response to treatment with 5 microg/mL of endotoxin. This impairment of NF-kappaB activation was found to be associated with depletion of latent NF-kappaB (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-kappaB available for activation by subsequent stimuli and thereby inhibit transcription of NF-kappaB-dependent genes. Limiting NF-kappaB-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.

MeSH Terms (8)

Animals Cell Line Drug Tolerance Endotoxins Gene Expression Regulation Macrophages, Alveolar NF-kappa B Rats

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