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Induction of endotoxin tolerance depletes nuclear factor‐κB and suppresses its activation in rat alveolar macrophages
Author(s) -
Blackwell Timothy S.,
Blackwell Thomas R.,
Christman John W.
Publication year - 1997
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.62.6.885
Subject(s) - biology , microbiology and biotechnology , macrophage , nfkb1 , immunology , transcription factor , biochemistry , in vitro , gene
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 μg/mL) resulted in decreased production of macrophage inflammatory protein‐2, tumor necrosis factor α, and nitric oxide compared to endotoxin‐sensitive cells. Suppressed mediator production by endotoxin‐tolerant cells was associated with impaired activation of nuclear factor‐κB (NF‐κB) in response to treatment with 5 μg/mL of endotoxin. This impairment of NF‐κB activation was found to be associated with depletion of latent NF‐κB (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‐κB available for activation by subsequent stimuli and thereby inhibit transcription of NF‐κB‐dependent genes. Limiting NF‐κB‐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. J. Leukoc. Biol . 62: 885–891; 1997.