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 () and Tadatsugu Taniguchi ()
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Akinori Takaoka: University of Tokyo
Hideyuki Yanai: University of Tokyo
Seiji Kondo: University of Toronto
Gordon Duncan: University of Toronto
Hideo Negishi: University of Tokyo
Tatsuaki Mizutani: University of Tokyo
Shin-ichi Kano: University of Tokyo
Kenya Honda: University of Tokyo
Yusuke Ohba: University of Tokyo
Tak W. Mak: University of Toronto
Tadatsugu Taniguchi: University of Tokyo

Nature, 2005, vol. 434, issue 7030, 243-249

Abstract: Abstract The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity1,2,3. All TLRs use the adaptor MyD88 for signalling4, 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-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.

Date: 2005
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DOI: 10.1038/nature03308

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