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Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors.

The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity. All TLRs use the adaptor MyD88 for signalling, but the mechanisms underlying the MyD88-mediated gene induction programme are as yet not fully understood. Here, we demonstrate that the transcription factor IRF-5 is generally involved downstream of the TLR-MyD88 signalling pathway for gene induction of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-12 and tumour-necrosis factor-alpha. In haematopoietic cells from mice deficient in the Irf5 gene (Irf5-/- mice), the induction of these cytokines by various TLR ligands is severely impaired, whereas interferon-alpha induction is normal. We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6, and that TLR activation results in the nuclear translocation of IRF-5 to activate cytokine gene transcription. Consistently, Irf5-/- mice show resistance to lethal shock induced by either unmethylated DNA or lipopolysaccharide, which correlates with a marked decrease in the serum levels of proinflammatory cytokines. Thus, our study identifies IRF-5 as a new, principal downstream regulator of the TLR-MyD88 signalling pathway and a potential target of therapeutic intervention to control harmful immune responses.

Pubmed ID: 15665823


  • Takaoka A
  • Yanai H
  • Kondo S
  • Duncan G
  • Negishi H
  • Mizutani T
  • Kano S
  • Honda K
  • Ohba Y
  • Mak TW
  • Taniguchi T



Publication Data

March 10, 2005

Associated Grants


Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation
  • Cytokines
  • Gene Deletion
  • Inflammation
  • Interferon Regulatory Factors
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Mice
  • Myeloid Differentiation Factor 88
  • Promoter Regions, Genetic
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Shock, Septic
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Transcription Factors
  • Up-Regulation