Abstract
Mutations of the NOD2 gene have been associated with an increased susceptibility to Crohn's disease, but the pathogenetic mechanisms mediated by NOD2 remain elusive. In the present study, we demonstrate that the 3020insC frameshift-mutation in the NOD2 gene associated with Crohn's disease results in defective release of IL-10 from blood mononuclear cells after stimulation with the Toll-like receptor (TLR)2 ligands, peptidoglycan and Pam3Cys-KKKK, but not with bacterial LPS, a TLR4 ligand. The potential pathophysiological significance of this finding in patients with Crohn's disease and who are homozygous for this NOD2 mutation was substantiated by the finding of decreased anti-inflammatory cytokine release when cells from these patients were stimulated with different species of Bacteroides, an enteric microorganism implicated in the pathogenesis of Crohn's disease. In conclusion, defective NOD2 function results in a pro-inflammatory cytokine bias after stimulation of mononuclear cells with TLR2 stimuli, and this could contribute to the overwhelming inflammation seen in Crohn's disease.
MeSH terms
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Animals
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Bacteroides / physiology
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CHO Cells
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cells, Cultured
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Cricetinae
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Crohn Disease / metabolism*
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Cytokines / biosynthesis
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Cytokines / metabolism*
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Genotype
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Humans
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Inflammation Mediators / metabolism*
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Interleukin-10 / biosynthesis
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Interleukin-10 / metabolism
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Intracellular Signaling Peptides and Proteins*
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Ligands
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Lipopolysaccharides / pharmacology
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / metabolism
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Membrane Glycoproteins / agonists*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Mice
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Nod2 Signaling Adaptor Protein
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Peptidoglycan / pharmacology
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Polymorphism, Genetic / genetics
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Receptors, Cell Surface / agonists*
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Signal Transduction / drug effects
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Carrier Proteins
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Cytokines
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Inflammation Mediators
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Intracellular Signaling Peptides and Proteins
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Ligands
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Lipopolysaccharides
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Membrane Glycoproteins
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NOD2 protein, human
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Nod2 Signaling Adaptor Protein
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Peptidoglycan
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Receptors, Cell Surface
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TLR2 protein, human
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TLR4 protein, human
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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Interleukin-10