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- Title
Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors.
- Authors
Takaoka, Akinori; Yanai, Hideyuki; Kondo, Seiji; Duncan, Gordon; Negishi, Hideo; Mizutani, Tatsuaki; Kano, Shin-Ichi; Honda, Kenya; Ohba, Yusuke; Mak, Tak W; Taniguchi, Tadatsugu
- 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
Nature, 2005, Vol 434, Issue 7030, p243
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature03308