Integrated regulation of Toll-like receptor responses by Notch and interferon-gamma pathways

Immunity. 2008 Nov 14;29(5):691-703. doi: 10.1016/j.immuni.2008.08.016. Epub 2008 Oct 30.

Abstract

Toll-like receptor (TLR) responses are regulated to avoid toxicity and achieve coordinated responses appropriate for the cell environment. We found that Notch and TLR pathways cooperated to activate canonical Notch target genes, including transcriptional repressors Hes1 and Hey1, and to increase production of canonical TLR-induced cytokines TNF, IL-6, and IL-12. Cooperation by these pathways to increase target gene expression was mediated by the Notch-pathway component and transcription factor RBP-J, which also contributed to lethality after endotoxin injection. TLR- and Notch-induced Hes1 and Hey1 attenuated IL-6 and IL-12 production. This Hes1- and Hey1-mediated feedback inhibitory loop was abrogated by interferon-gamma (IFN-gamma), which blocked TLR-induced activation of canonical Notch target genes by inhibiting Notch2 signaling and downstream transcription. These findings identify new immune functions for RBP-J, Hes, and Hey proteins and provide insights into mechanisms by which Notch, TLR, and IFN-gamma signals are integrated to modulate specific effector functions in macrophages.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Gene Expression Regulation*
  • Gene Knockdown Techniques
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / immunology
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism*
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / immunology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Receptors, Notch / metabolism*
  • Repressor Proteins / metabolism
  • Signal Transduction*
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism*
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hairy, HRT1 protein
  • Homeodomain Proteins
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Interleukin-6
  • Lipopolysaccharides
  • Receptors, Notch
  • Repressor Proteins
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma

Associated data

  • GEO/GSE11864