Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages

Nat Immunol. 2011 May 22;12(7):607-15. doi: 10.1038/ni.2043.


Endotoxin tolerance, a key mechanism for suppressing excessive inflammatory cytokine production, is induced by prior exposure of macrophages to Toll-like receptor (TLR) ligands. Induction of cross-tolerance to endotoxin by endogenous cytokines has not been investigated. Here we show that prior exposure to tumor necrosis factor (TNF) induced a tolerant state in macrophages, with less cytokine production after challenge with lipopolysaccharide (LPS) and protection from LPS-induced death. TNF-induced cross-tolerization was mediated by suppression of LPS-induced signaling and chromatin remodeling. TNF-induced cross-tolerance was dependent on the kinase GSK3, which suppressed chromatin accessibility and promoted rapid termination of signaling via the transcription factor NF-κB by augmenting negative feedback by the signaling inhibitors A20 and IκBα. Our results demonstrate an unexpected homeostatic function for TNF and a GSK3-mediated mechanism for the prevention of prolonged and excessive inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chromatin Assembly and Disassembly / drug effects
  • Chromatin Assembly and Disassembly / immunology
  • Cysteine Endopeptidases / immunology
  • Cysteine Endopeptidases / metabolism
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Endotoxins / immunology*
  • Female
  • Glycogen Synthase Kinase 3 / immunology*
  • I-kappa B Proteins / immunology
  • I-kappa B Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipopolysaccharides / immunology
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tumor Necrosis Factor-alpha / immunology*


  • Cytokines
  • Endotoxins
  • I-kappa B Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Nfkbia protein, mouse
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Glycogen Synthase Kinase 3
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse