ABSTRACT
The mechanism by which mutations in NOD2 predispose to Crohn's disease (CD) is incompletely understood. In mice, NOD2 has been found to function as a negative regulator of Toll-like receptor 2 (TLR2) signaling. In contrast, studies in humans so far showed no negative regulatory interaction between NOD2 and TLR2, and in fact suggest a synergistic effect between the two. Here, we show that this interaction is dose dependent. Adding low doses of muramyl dipeptide (MDP) to TLR2 primed monocytes results in a significant increase in cytokine production, whereas adding higher doses of MDP led to a striking downregulation of the responses. This downregulation by high-dose MDP does not occur in monocytes from NOD2-deficient patients. The inhibitory role of NOD2 at high concentrations of MDP implicates a safety mechanism to prevent exaggerated antibacterial immune responses in the gut to high or perpetuating bacterial load. This regulatory mechanism is lost in NOD2-deficient CD patients.
Subject(s)
Crohn Disease/genetics , Gene Expression Regulation/genetics , Nod2 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/metabolism , Toll-Like Receptor 2/metabolism , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Crohn Disease/immunology , Gene Expression Regulation/drug effects , Genotype , Humans , Monocytes/metabolism , Mutation/geneticsABSTRACT
Nuclear factor kappaB (NF-kappaB) designates a group of critical transcription factors involved in a variety of immunologic and/or inflammatory processes. Conceivably, genes involved in the NF-kappaB pathway make interesting candidate genes for chronic inflammatory disorders, including the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC). In two mouse models of colitis, strong linkage has been observed with a locus on chromosome 3 that harbours the Nfkb1 gene. In addition, a polymorphism in the promoter region of the human NFKB1 gene was found to be associated with susceptibility to UC. In this study, we searched to confirm this previously found association in IBD in a different population. Allele and genotype frequencies of the -94 ins/delATTG polymorphism were determined in 266 unrelated Dutch Caucasian IBD patients (127 UC, 139 CD), and 155 matched healthy controls. The allele frequency of the deletion was significantly higher in UC patients (P = 0.019), but not in CD patients, compared to healthy controls, and the UC patients homozygous for the -94 ATTG deletion had a younger age of onset. Our findings confirm the previously found association between this polymorphism and susceptibility to UC in an independent study population and adds further evidence for the role of this gene in disease susceptibility.
Subject(s)
Colitis, Ulcerative/genetics , Crohn Disease/genetics , Genetic Predisposition to Disease , NF-kappa B p50 Subunit/genetics , Polymorphism, Genetic , Promoter Regions, Genetic/genetics , Adult , Animals , Case-Control Studies , Female , Humans , Male , MiceABSTRACT
Celiac disease (CD) is a common gastro-intestinal disorder resulting from permanent intolerance to wheat gliadins and related proteins in rye and barley. In addition to the strong genetic association with HLA-DQ2 and HLA-DQ8, a genetic region on chromosomes 5 (CELIAC2) has been identified that harbours a susceptibility gene for CD. The gene(s) responsible for this association, however, remains to be identified. In the present study we evaluated polymorphisms in the genes encoding interleukin-12 p40 (IL12B) and interferon regulatory factor 1 (IRF1). Both genes are located in the celiac2 region, and have key roles in inducing interferon (IFN)-gamma secreting T helper 1 (Th1) cells, one of the immunological hallmarks of CD. The frequencies of a TaqI gene polymorphism in the 3' UTR of IL12B and a HinfI gene polymorphism in the 3' UTR of IRF1 were studied in 258 Dutch CD patients and 237 ethnically matched healthy controls. The transmission of the polymorphic variants from parents to affected child was determined in 123 families with at least one affected child. The frequencies of the IL12B TaqI gene polymorphism and the IRF1 HinfI gene polymorphism did not differ significantly between patients and controls. In addition, in the family study, no deviation from the expected transmission from parents to affected child of any of the polymorphic variants was found. The IL12B TaqI and the IRF1 HinfI gene polymorphisms do not appear to be involved in susceptibility to CD. Further studies on the factors that drive the Th1 immunopathology in CD are required.
