Essential role of IRF-3 in lipopolysaccharide-induced interferon-beta gene expression and endotoxin shock.
Type I interferons (IFN-alpha/beta) 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-beta 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-beta 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-beta, 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.
Sakaguchi
Shinya
S
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Negishi
Hideo
H
Asagiri
Masataka
M
Nakajima
Chigusa
C
Mizutani
Tatsuaki
T
Takaoka
Akinori
A
Honda
Kenya
K
Taniguchi
Tadatsugu
T
D000818:Animals; D003513:Cycloheximide / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003713:Dendritic Cells; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016899:Interferon-beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D015854:Up-Regulation
D016207:Cytokines; D004268:DNA-Binding Proteins; D004731:Endotoxins; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; D008070:Lipopolysaccharides; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; D016899:Interferon-beta; D003513:Cycloheximide; D008156:Luciferases