Abstract
Interferon regulatory factor (IRF) 3 is a transcription factor that binds the interferon-sensitive response element (ISRE) and is activated by Toll-like receptor 3 (TLR3) and TLR4. We have found that a dominant negative form of I kappa B kinase 2 and a mutant form of I kappa B, which acts as a super-repressor of NF-kappa B, blocked activation of the ISRE by the TLR4 ligand lipopolysaccharide but not the TLR3 ligand poly(I-C). TLR4 failed to activate the ISRE in mouse embryonic fibroblasts bearing a targeted deletion of p65, whereas the response to TLR3 in these cells was normal. The p65 subunit of NF-kappa B was detected in the lipopolysaccharide-activated but not poly(I-C)-activated ISRE-binding complex. Finally, p65 promoted transactivation of gene expression by IRF-3. These results therefore indicate that IRF-3-mediated activation of the ISRE by TLR4 but not TLR3 requires the p65 subunit of NF-kappa B.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Embryo, Mammalian / cytology
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Humans
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I-kappa B Kinase
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I-kappa B Proteins / genetics
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Interferon Regulatory Factor-3
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Ligands
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Lipopolysaccharides / pharmacology
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Membrane Glycoproteins / physiology*
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Mice
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Mutation
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NF-kappa B / physiology*
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Poly I-C / pharmacology
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Protein Serine-Threonine Kinases / genetics
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Receptors, Cell Surface / physiology*
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Repressor Proteins
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Response Elements*
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factor RelA
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcriptional Activation
Substances
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DNA-Binding Proteins
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I-kappa B Proteins
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Irf3 protein, mouse
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Ligands
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Lipopolysaccharides
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Membrane Glycoproteins
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NF-kappa B
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Receptors, Cell Surface
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Repressor Proteins
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TLR3 protein, human
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TLR4 protein, human
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factor RelA
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Transcription Factors
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse
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Poly I-C