Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cycloheximide / metabolism
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Cytokines / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Dendritic Cells
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Dose-Response Relationship, Drug
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Endotoxins / pharmacology*
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Gene Expression Regulation*
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Genes, Dominant
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Interferon-beta / metabolism*
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Lipopolysaccharides / metabolism*
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Luciferases / metabolism
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Mice
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Protein Synthesis Inhibitors / pharmacology
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcriptional Activation
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Up-Regulation
Substances
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Cytokines
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DNA-Binding Proteins
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Endotoxins
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Irf3 protein, mouse
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Irf7 protein, mouse
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Lipopolysaccharides
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Protein Synthesis Inhibitors
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RNA, Messenger
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Transcription Factors
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Interferon-beta
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Cycloheximide
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Luciferases