Abstract
Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor kappaB (NF-kappaB) and antibacterial defenses, but CD clinical specimens display elevated NF-kappaB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-kappaB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1beta (IL-1beta). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-kappaB activation and IL-1beta secretion.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylmuramyl-Alanyl-Isoglutamine / immunology
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Animals
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Anti-Bacterial Agents / pharmacology
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Apoptosis
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Bacteria / immunology
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Cells, Cultured
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Colitis / immunology
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Colitis / pathology
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Colon / immunology*
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Colon / microbiology
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Crohn Disease / genetics
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Crohn Disease / immunology*
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Cytokines / biosynthesis
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Cytokines / genetics
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Dextran Sulfate / pharmacology
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Interleukin-1 / metabolism*
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Intestinal Mucosa / immunology
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / physiology*
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Lipopolysaccharides / immunology
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Macrophage Activation
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Macrophages / immunology*
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Macrophages / metabolism
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Mice
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Mutation
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NF-kappa B / metabolism*
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Nod2 Signaling Adaptor Protein
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Peptidoglycan / immunology
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Signal Transduction
Substances
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Anti-Bacterial Agents
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Cytokines
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Interleukin-1
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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NF-kappa B
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Nod2 Signaling Adaptor Protein
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Nod2 protein, mouse
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Peptidoglycan
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Acetylmuramyl-Alanyl-Isoglutamine
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Dextran Sulfate