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

266 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

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Keywords

  • IFN regulatory factor
  • Macrophage
  • MyD88

ASJC Scopus subject areas

  • General

Cite this

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, 102(44), 15989-15994. https://doi.org/10.1073/pnas.0508327102