Franke, A, Balschun, T, Karlsen, TH, Sventoraityte, J, Nikolaus, S, Mayr, G et al.; IBSEN study group.. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 40: 1319-1323

Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel 24105, Germany.
Nature Genetics (Impact Factor: 29.35). 11/2008; 40(11):1319-23. DOI: 10.1038/ng.221
Source: PubMed


Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 x 10(-12); OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.

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    • "Our study indicated that EH and all the size fractions of casein hydrolysate downregulated IL-10 expression in porcine colonic explant. A genome-wide association study identified IL-10 as a susceptibility locus for the development of IBD in humans (Franke et al. 2008). It has also been reported that local levels of IL-10 mRNA were higher in mucosa of IBD patients (Niessner and Volk 2008). "
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    ABSTRACT: Bioactive milk peptides are reported to illicit a range of physiological benefits and have been proposed as potential functional food ingredients. The objective of this study was to characterize the anti-inflammatory properties of sodium caseinate (NaCAS), its enzyme hydrolysate (EH) and peptide-enriched fractions (5 kDa retentate [R], 1 kDaR and 1 kDa permeate [P]), both in vitro using a Caco-2 cell line, and also ex vivo using a porcine colonic tissue explant system. Caco-2 cells were stimulated with tumour necrosis factor alpha (TNFα) and co-treated with casein hydrolysates for 24 h. Following this, interleukin (IL)-8 concentrations in the supernatant were measured using enzyme-linked immunosorbent assay. Porcine colonic tissue was stimulated with lipopolysaccharide and co-treated with casein hydrolysates for 3 h. The expression of a panel of inflammatory cytokines was measured using qPCR. While dexamethasone reduced the IL-8 concentration by 41.6%, the 1 kDaR and 1 kDaP fractions reduced IL-8 by 68.7% and 66.1%, respectively, relative to TNFα-stimulated Caco-2 cells (P < 0.05). In the ex vivo system, only the 1 kDaR fraction elicited a decrease in IL1-α, IL1-β, IL-8, TGF-β and IL-10 expression (P < 0.05). This study provides evidence that the bioactive peptides present in the 1 kDaR fraction of the NaCAS hydrolysate possess anti-inflammatory properties in vitro and ex vivo. Further in vivo analysis of the anti-inflammatory properties of the 1 kDaR is proposed.
    Full-text · Article · Nov 2014 · Food Science & Nutrition
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    • "Recently, IL-10 has been shown to play a central role in goblet cell homeostasis by suppressing the ER stress and promoting intestinal mucus production [2], [9], [14]. Moreover, IL-10 polymorphisms and rarer mutations in the IL-10 and IL-10R genes have been associated with inflammatory bowel diseases (IBD) [15], [16] and severe enterocolitis in infants [17], respectively. Furthermore, mice lacking IL-10 spontaneously develop colon and ileum inflammation similar to Crohn’s disease [18]. "
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    ABSTRACT: Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the rectum which progressively extents. Its etiology remains unknown and the number of treatments available is limited. Studies of UC patients have identified an unbalanced endoplasmic reticulum (ER) stress in the non-inflamed colonic mucosa. Animal models with impaired ER stress are sensitive to intestinal inflammation, suggesting that an unbalanced ER stress could cause inflammation. However, there are no ER stress-regulating strategies proposed in the management of UC partly because of the lack of relevant preclinical model mimicking the disease. Here we generated the IL10/Nox1dKO mouse model which combines immune dysfunction (IL-10 deficiency) and abnormal epithelium (NADPH oxidase 1 (Nox1) deficiency) and spontaneously develops a UC-like phenotype with similar complications (colorectal cancer) than UC. Our data identified an unanticipated combined role of IL10 and Nox1 in the fine-tuning of ER stress responses in goblet cells. As in humans, the ER stress was unbalanced in mice with decreased eIF2α phosphorylation preceding inflammation. In IL10/Nox1dKO mice, salubrinal preserved eIF2α phosphorylation through inhibition of the regulatory subunit of the protein phosphatase 1 PP1R15A/GADD34 and prevented colitis. Thus, this new experimental model highlighted the central role of epithelial ER stress abnormalities in the development of colitis and defined the defective eIF2α pathway as a key pathophysiological target for UC. Therefore, specific regulators able to restore the defective eIF2α pathway could lead to the molecular remission needed to treat UC.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Genome-wide association studies have identified SNPs flanking the IL-10 gene to be linked to UC (Franke et al., 2008). IL-10-deficient mice exhibit intolerance to their intestinal microbiota, have altered responses to inflammatory or autoimmune stimuli and develop spontaneous enterocolitis and adenocarcinoma (Sturlan et al., 2001). "
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    ABSTRACT: The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases (IBD) have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of IBD have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn's disease (CD) and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of IBD.
    Full-text · Article · Feb 2014 · Frontiers in Cellular and Infection Microbiology
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