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

674 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

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Toll-Like Receptors
Cytokines
Genes
TNF Receptor-Associated Factor 6
Interferon Regulatory Factors
Interleukin-12
Interferons
Lipopolysaccharides
Shock
Interleukin-6
Tumor Necrosis Factor-alpha
Ligands
DNA
Serum

ASJC Scopus subject areas

  • General

Cite this

Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., ... 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

Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. / Takaoka, Akinori; Yanai, Hideyuki; Kondo, Seiji; Duncan, Gordon; Negishi, Hideo; Mizutani, Tatsuaki; Kano, Shin Ichi; Honda, Kenya; Ohba, Yusuke; Mak, Tak W.; Taniguchi, Tadatsugu.

In: Nature, Vol. 434, No. 7030, 10.03.2005, p. 243-249.

Research output: Contribution to journalArticle

Takaoka, A, Yanai, H, Kondo, S, Duncan, G, Negishi, H, Mizutani, T, Kano, SI, Honda, K, Ohba, Y, Mak, TW & Taniguchi, T 2005, 'Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors', Nature, vol. 434, no. 7030, pp. 243-249. https://doi.org/10.1038/nature03308
Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005 Mar 10;434(7030):243-249. https://doi.org/10.1038/nature03308
Takaoka, Akinori ; Yanai, Hideyuki ; Kondo, Seiji ; Duncan, Gordon ; Negishi, Hideo ; Mizutani, Tatsuaki ; Kano, Shin Ichi ; Honda, Kenya ; Ohba, Yusuke ; Mak, Tak W. ; Taniguchi, Tadatsugu. / Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. In: Nature. 2005 ; Vol. 434, No. 7030. pp. 243-249.
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