Integral Role of IRF-5 in the Gene Induction Programme Activated by Toll-like Receptors

Nature. 2005 Mar 10;434(7030):243-9. doi: 10.1038/nature03308. Epub 2005 Jan 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Cytokines
  • Interferon Regulatory Factors
  • Irf5 protein, mouse
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Transcription Factors