Abstract
Toll-like receptors (TLRs) trigger the production of inflammatory cytokines and shape adaptive and innate immunity to pathogens. We report the identification of B cell leukemia (Bcl)-3 as an essential negative regulator of TLR signaling. By blocking ubiquitination of p50, a member of the nuclear factor (NF)-kappaB family, Bcl-3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl-3-deficient mice and cells were found to be hypersensitive to TLR activation and unable to control responses to lipopolysaccharides. Thus, p50 ubiquitination blockade by Bcl-3 limits the strength of TLR responses and maintains innate immune homeostasis. These findings indicate that the p50 ubiquitination pathway can be selectively targeted to control deleterious inflammatory diseases.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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B-Cell Lymphoma 3 Protein
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Cell Line
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Cells, Cultured
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DNA / metabolism
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Female
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Half-Life
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Immune Tolerance
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Immunity, Innate
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Lipopolysaccharides / immunology
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Macrophage Activation
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Macrophages, Peritoneal / immunology*
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Macrophages, Peritoneal / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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NF-kappa B p50 Subunit / metabolism*
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Signal Transduction*
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Toll-Like Receptors / metabolism*
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Transcription Factor RelA / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Ubiquitin / metabolism
Substances
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B-Cell Lymphoma 3 Protein
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Bcl3 protein, mouse
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Lipopolysaccharides
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NF-kappa B p50 Subunit
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Proto-Oncogene Proteins
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Rela protein, mouse
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Toll-Like Receptors
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Transcription Factor RelA
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Ubiquitin
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DNA