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Crohn's disease patients homozygous for the 3020insC NOD2 mutation have a defective NOD2/TLR4 cross-tolerance to intestinal stimuli
- Source :
- Immunology, 123, 4, pp. 600-5, Immunology, 123, 600-5
- Publication Year :
- 2008
-
Abstract
- Contains fulltext : 69346.pdf (Publisher’s version ) (Closed access) Mutations in nucleotide-binding oligomerization domain-2 (NOD2), leading to defective recognition of bacterial peptidoglycans, are associated with Crohn's disease. The underlying mechanism that results in increased inflammation in the guts of the patients bearing NOD2 mutations is still unclear. We hypothesized that NOD2 engagement leads to cross-tolerance to stimulation of Toll-like receptors (TLR), and we investigated whether patients with Crohn's disease who bear NOD2 mutations display a disturbed NOD2/TLR cross-tolerance. Peripheral blood mononuclear cells preincubated with NOD2 ligands were specifically down-regulated for the production of tumour necrosis factor-alpha (TNF-alpha) induced by the TLR4 ligand lipopolysaccharide, as well as by intestinal microorganisms, whereas the production of anti-inflammatory cytokines was not modulated. While in cells isolated from patients with Crohn's disease with the wild-type NOD2 allele, the NOD2 engagement led to a similar cross-tolerance to TLR4-dependent stimulation of TNF-alpha, the cross-tolerance between NOD2 and TLR4 was absent in the cells of five patients homozygous for the 3020insC NOD2 mutation, leading to uninhibited release of TNF-alpha by TLR4 ligands and intestinal bacteria. In conclusion, we propose the absence of NOD2/TLR4 cross-tolerance as a central mechanism for the increased susceptibility to Crohn's disease in individuals with NOD2 mutations.
- Subjects :
- Lipopolysaccharide
Colon
Immunology
Nod2 Signaling Adaptor Protein
Membrane transport and intracellular motility [NCMLS 5]
Stimulation
Inflammation
Peptidoglycan
Biology
Peripheral blood mononuclear cell
Auto-immunity, transplantation and immunotherapy [N4i 4]
Invasive mycoses and compromised host [N4i 2]
chemistry.chemical_compound
Crohn Disease
NOD2
Immune Tolerance
medicine
Perception and Action [DCN 1]
Humans
Immunology and Allergy
Genetic Predisposition to Disease
Intestinal Mucosa
Molecular gastro-enterology and hepatology [IGMD 2]
Receptor
Cells, Cultured
Chronic inflammation and autoimmunity [UMCN 4.2]
Crohn's disease
Bacteria
Tumor Necrosis Factor-alpha
Original Articles
medicine.disease
digestive system diseases
Toll-Like Receptor 4
Pathogenesis and modulation of inflammation [N4i 1]
Enterocytes
chemistry
Genetic defects of metabolism [UMCN 5.1]
Mutation
TLR4
Microbial pathogenesis and host defense [UMCN 4.1]
medicine.symptom
Infection and autoimmunity [NCMLS 1]
Immunity, infection and tissue repair [NCMLS 1]
Subjects
Details
- ISSN :
- 00192805
- Database :
- OpenAIRE
- Journal :
- Immunology, 123, 4, pp. 600-5, Immunology, 123, 600-5
- Accession number :
- edsair.doi.dedup.....a6a6fd97984cd8be1f9d3c6458af75c4