Essential role of IRF-3 in lipopolysaccharide-induced interferon-β gene expression and endotoxin shock

Shinya Sakaguchi, Hideo Negishi, Masataka Asagiri, Chigusa Nakajima, Tatsuaki Mizutani, Akinori Takaoka, Kenya Honda, Tadatsugu Taniguchi

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

Type I interferons (IFN-α/β) affect many aspects of immune responses. Many pathogen-associated molecules, including bacterial lipopolysaccharide (LPS) and virus-associated double-stranded RNA, induce IFN gene expression through activation of distinct Toll-like receptors (TLRs). Although much has been studied about the activation of the transcription factor IRF-3 and induction of IFN-β gene by the LPS-mediated TLR4 signaling, definitive evidence is missing about the actual role of IRF-3 in LPS responses in vitro and in vivo. Using IRF-3 deficient mice, we show here that IRF-3 is indeed essential for the LPS-mediated IFN-β gene induction. Loss of IRF-3 also affects the expression of profile of other cytokine/chemokine genes. We also provide evidence that the LPS/TLR4 signaling activates IRF-7 to induce IFN-β, if IRF-7 is induced by IFNs prior to LPS simulation. Finally, the IRF-3-deficient mice show resistance to LPS-induced endotoxin shock. These results place IRF-3 as a molecule central to LPS/TLR4 signaling.

Original languageEnglish
Pages (from-to)860-866
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume306
Issue number4
DOIs
Publication statusPublished - 2003 Jul 11
Externally publishedYes

Keywords

  • Endotoxin shock
  • IFN-α/β
  • IRF-3
  • IRF-7
  • LPS
  • TLR4

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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