IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling Academic Article uri icon


MeSH Major

  • Chromatin Assembly and Disassembly
  • Endotoxins
  • Immune Tolerance
  • Interferon-gamma
  • Toll-Like Receptors


  • An important mechanism by which IFN-γ primes macrophages for enhanced innate immune responses is abrogation of feedback inhibitory pathways. Accordingly, IFN-γ abrogates endotoxin tolerance, a major negative feedback loop that silences expression of inflammatory cytokine genes in macrophages previously exposed to endotoxin/Toll-like receptor (TLR) ligands. Mechanisms by which IFN-γ inhibits endotoxin tolerance have not been elucidated. Here, we show that pretreatment with IFN-γ prevented tolerization of primary human monocytes and restored TLR4-mediated induction of various proinflammatory cytokines, including IL-6 and TNFα. Surprisingly, IFN-γ did not alter proximal TLR4 signaling defects in tolerized monocytes. Instead, IFN-γ blocked tolerance-associated down-regulation of IL6 and TNF transcription, RNA polymerase II recruitment, and NF-κB and CCAAT/enhancer-binding protein β transcription factor binding to the IL6 and TNF promoters in tolerized monocytes. The mechanism by which IFN-γ restored IL6 expression was by facilitating TLR4-induced recruitment of chromatin remodeling machinery to the IL6 promoter and promoting IL6 locus accessibility in tolerized monocytes. Our results suggest that IFN-γ overcomes endotoxin tolerance by facilitating TLR-induced chromatin remodeling to allow expression of proinflammatory genes. These results identify a mechanism by which IFN-γ promotes activation of macrophages and highlight the importance of chromatin remodeling and transcriptional control in the regulation of inflammatory cytokine production in tolerant and activated macrophages.

publication date

  • November 9, 2010



  • Academic Article



  • eng

PubMed Central ID

  • PMC2984206

Digital Object Identifier (DOI)

  • 10.1073/pnas.1007816107

PubMed ID

  • 20974955

Additional Document Info

start page

  • 19438

end page

  • 43


  • 107


  • 45