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

Akinori Takaoka, Hideyuki Yanai, Seiji Kondo, Gordon Duncan, Hideo Negishi, Tatsuaki Mizutani, Shin Ichi Kano, Kenya Honda, Yusuke Ohba, Tak W. Mak, Tadatsugu Taniguchi

Research output: Contribution to journalArticle

701 Citations (Scopus)

Abstract

The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity1-3. All TLRs use the adaptor MyD88 for signalling4, but the mechanisms underlying the MyD88-mediated gene induction programme are as yet not fully under-stood. 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-α. 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-α 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.

Original languageEnglish
Pages (from-to)243-249
Number of pages7
JournalNature
Volume434
Issue number7030
DOIs
Publication statusPublished - 2005 Mar 10
Externally publishedYes

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors'. Together they form a unique fingerprint.

  • Cite this

    Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., Kano, S. I., Honda, K., Ohba, Y., Mak, T. W., & Taniguchi, T. (2005). Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature, 434(7030), 243-249. https://doi.org/10.1038/nature03308