1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
2. Campbell Family Institute of Breast Cancer Research, University of Toronto, 610 University Avenue, Room 7-411, Toronto, Ontario M5G 2M9, Canada
3. Information and Cell Function, PRESTO, JST, Kawaguchi, Saitama 332-0012, Japan
4. These authors contributed equally to this work

Correspondence to: Tak W. Mak²Tadatsugu Taniguchi¹ Correspondence and requests for materials should be addressed to T.W.M. (Email: tmak@uhnres.utroronto.ca) or T.T. (Email: tada@m.u-tokyo.ac.jp).

Abstract

The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity^{1, 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-. 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- 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.

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