IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins

Immunity. 2006 May;24(5):563-74. doi: 10.1016/j.immuni.2006.02.014.


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 types

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

MeSH terms

  • Animals
  • Arthritis / immunology
  • CREB-Binding Protein / immunology*
  • CREB-Binding Protein / metabolism
  • Disease Models, Animal
  • Electrophoretic Mobility Shift Assay
  • Enzyme Activation / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Glycogen Synthase Kinase 3 / immunology*
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / immunology
  • Mice
  • Models, Immunological
  • Peritonitis / immunology
  • RNA, Messenger / analysis
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 2 / immunology*
  • Toll-Like Receptor 2 / metabolism
  • Transcription Factor AP-1 / immunology*
  • Transcription Factor AP-1 / metabolism
  • Transfection


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