IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Academic Article uri icon

Overview

abstract

  • The control of IL-10 production and mechanisms that mediate synergy between IFN-gamma and TLR ligands are not well understood. We report that IFN-gamma augments induction of TNFalpha by TLR ligands, immune complexes, and zymosan by suppressing IL-10 production and thereby interrupting Stat3-mediated feedback inhibition. IFN-gamma altered TLR2-induced signal transduction by increasing GSK3 activity and suppressing MAPK activation, leading to diminished IL-10 production. Inhibition of GSK3 or ablation of the GSK3beta gene ameliorated TLR2-induced peritonitis and arthritis. IFN-gamma suppressed the activity of CREB and AP-1, transcription factors that induce IL-10 expression and are regulated in part by MAPKs and GSK3. These results yield insight into mechanisms by which IFN-gamma regulates IL-10 production and TLR2-mediated inflammatory responses and identify inhibition of CREB and AP-1 as part of the macrophage response to IFN-gamma. GSK3 and CREB/AP-1 are key players in integrating IFN-gamma and TLR2 responses in innate immunity and inflammation.

publication date

  • May 1, 2006

Research

keywords

  • CREB-Binding Protein
  • Glycogen Synthase Kinase 3
  • Interferon-gamma
  • Interleukin-10
  • Toll-Like Receptor 2
  • Transcription Factor AP-1

Identity

Scopus Document Identifier

  • 33646595287

Digital Object Identifier (DOI)

  • 10.1016/j.immuni.2006.02.014

PubMed ID

  • 16713974

Additional Document Info

volume

  • 24

issue

  • 5