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

Academic Article

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.

    • Authors

    Published In

  • Nature  Journal

    • Keywords

  • 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

    • Digital Object Identifier (doi)

    Author List

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

    • Start Page

  • 243

    • End Page

  • 249

    • Volume

  • 434

    • Issue

  • 7030