Integrated regulation of Toll-like receptor responses by Notch and interferon-gamma pathways. Academic Article uri icon

Overview

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 date

  • October 30, 2008

Research

keywords

  • Gene Expression Regulation
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Interferon-gamma
  • Receptors, Notch
  • Signal Transduction
  • Toll-Like Receptors

Identity

PubMed Central ID

  • PMC2585039

Scopus Document Identifier

  • 55349128861

Digital Object Identifier (DOI)

  • 10.1016/j.immuni.2008.08.016

PubMed ID

  • 18976936

Additional Document Info

volume

  • 29

issue

  • 5