Negative regulation of Toll-like-receptor signaling by IRF-4

Hideo Negishi, Yusuke Ohba, Hideyuki Yanai, Akinori Takaoka, Kiri Honma, Katsuyuki Yui, Toshifumi Matsuyama, Tadatsugu Taniguchi, Kenya Honda

Research output: Contribution to journalArticle

260 Citations (Scopus)

Abstract

The recognition of microbial components by Toll-like receptors (TLRs) is an event central to the activation of innate and adaptive immune systems. TLR activation triggers the induction of downstream target genes, wherein the TLR-interacting adaptor molecule MyD88 recruits various signaling molecules and transcription factors. Two members of the IFN regulatory factor (IRF) family of transcription factors, IRF-5 and IRF-7, interact with MyD88 and induce proinflammatory cytokines and type I IFNs, respectively. Here, we show that IRF-4 also interacts with MyD88 and acts as a negative regulator of TLR signaling. IRF-4 mRNA is induced by TLR activation, and IRF-4 competes with IRF-5, but not with IRF-7, for MyD88 interaction. The TLR-dependent induction of proinflammatory cytokines is markedly enhanced in peritoneal macrophages from mice deficient in the Irf4 gene, whereas the induction is inhibited by the ectopic expression of IRF-4 in a macrophage cell line. The critical function of IRF-4 in TLR signaling in vivo is underscored by the observation that Irf4-deficient mice show hypersensitivity to DNA-induced shock, with elevated serum proinflammatory cytokine levels. This study may provide an insight into the complex regulatory mechanisms of MyD88 signaling by IRFs.

Original languageEnglish
Pages (from-to)15989-15994
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number44
DOIs
Publication statusPublished - 2005 Nov 1
Externally publishedYes

Fingerprint

Toll-Like Receptors
Cytokines
Transcription Factors
Toll-Like Receptor 4
Peritoneal Macrophages
Genes
Immune System
Shock
Hypersensitivity
Macrophages
Cell Line
Messenger RNA
DNA
Serum

Keywords

  • IFN regulatory factor
  • Macrophage
  • MyD88

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Negative regulation of Toll-like-receptor signaling by IRF-4. / Negishi, Hideo; Ohba, Yusuke; Yanai, Hideyuki; Takaoka, Akinori; Honma, Kiri; Yui, Katsuyuki; Matsuyama, Toshifumi; Taniguchi, Tadatsugu; Honda, Kenya.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 44, 01.11.2005, p. 15989-15994.

Research output: Contribution to journalArticle

Negishi, H, Ohba, Y, Yanai, H, Takaoka, A, Honma, K, Yui, K, Matsuyama, T, Taniguchi, T & Honda, K 2005, 'Negative regulation of Toll-like-receptor signaling by IRF-4', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 44, pp. 15989-15994. https://doi.org/10.1073/pnas.0508327102
Negishi, Hideo ; Ohba, Yusuke ; Yanai, Hideyuki ; Takaoka, Akinori ; Honma, Kiri ; Yui, Katsuyuki ; Matsuyama, Toshifumi ; Taniguchi, Tadatsugu ; Honda, Kenya. / Negative regulation of Toll-like-receptor signaling by IRF-4. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 44. pp. 15989-15994.
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