The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling

J Biol Chem. 2005 Apr 29;280(17):17005-12. doi: 10.1074/jbc.M412584200. Epub 2005 Jan 28.

Abstract

Interferon regulatory factors (IRFs) are critical components of virus-induced immune activation and type I interferon regulation. IRF3 and IRF7 are activated in response to a variety of viruses or after engagement of Toll-like receptor (TLR) 3 and TLR4 by double-stranded RNA and lipopolysaccharide, respectively. The activation of IRF5, is much more restricted. Here we show that in contrast to IRF3 and IRF7, IRF5 is not a target of the TLR3 signaling pathway but is activated by TLR7 or TLR8 signaling. We also demonstrate that MyD88, interleukin 1 receptor-associated kinase 1, and tumor necrosis factor receptor-associated factor 6 are required for the activation of IRF5 and IRF7 in the TLR7 signaling pathway. Moreover, ectopic expression of IRF5 enabled type I interferon production in response to TLR7 signaling, whereas knockdown of IRF5 by small interfering RNA reduced type I interferon induction in response to the TLR7 ligand, R-848. IRF5 and IRF7, therefore, emerge from these studies as critical mediators of TLR7 signaling.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation / metabolism
  • Biological Assay
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology*
  • Dose-Response Relationship, Drug
  • Electroporation
  • Genes, Reporter
  • Glutathione Transferase / metabolism
  • Humans
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon Regulatory Factors
  • Interferon Type I / metabolism
  • Ligands
  • Lipopolysaccharides / metabolism
  • Membrane Glycoproteins / metabolism*
  • Microscopy, Confocal
  • Models, Biological
  • Myeloid Differentiation Factor 88
  • Phosphorylation
  • RNA Interference
  • RNA, Double-Stranded / metabolism
  • RNA, Small Interfering / metabolism
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Time Factors
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Toll-Like Receptors
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • DNA-Binding Proteins
  • IRF3 protein, human
  • IRF5 protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon Regulatory Factors
  • Interferon Type I
  • Ligands
  • Lipopolysaccharides
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myeloid Differentiation Factor 88
  • RNA, Double-Stranded
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Recombinant Fusion Proteins
  • TLR3 protein, human
  • TLR4 protein, human
  • TLR7 protein, human
  • TLR8 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Toll-Like Receptors
  • Transcription Factors
  • Glutathione Transferase