Induction of endotoxin tolerance depletes nuclear factor-kappaB 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 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.
Blackwell
T S
TS
Department of Medicine, Vanderbilt University School of Medicine, and Department of Veterans Affairs Medical Center, Nashville, Tennessee 37232-2650, USA.
Blackwell
T R
TR
Christman
J W
JW
D000818:Animals; D002460:Cell Line; D004361:Drug Tolerance; D004731:Endotoxins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051381:Rats
D004731:Endotoxins; D016328:NF-kappa B