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Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis.

ABSTRACT: Bcl-3 is an atypical NF-?B family member that regulates NF-?B-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear. Here we show that Bcl-3 expression levels in colonic T cells correlate with disease manifestation in patients with inflammatory bowel disease. Mice with T-cell-specific overexpression of Bcl-3 develop severe colitis that can be attributed to defective Treg cell development and function, leading to the infiltration of immune cells such as pro-inflammatory ??T cells, but not ?? T cells. In Treg cells, Bcl-3 associates directly with NF-?B p50 to inhibit DNA binding of p50/p50 and p50/p65 NF-?B dimers, thereby regulating NF-?B-mediated gene expression. This study thus reveals intrinsic functions of Bcl-3 in Treg cells, identifies Bcl-3 as a potential prognostic marker for colitis and illustrates the mechanism by which Bcl-3 regulates NF-?B activity in Tregs to prevent colitis.

SUBMITTER: Reißig S

PROVIDER: S-EPMC5414353 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis.

Reißig Sonja S Tang Yilang Y Nikolaev Alexei A Gerlach Katharina K Wolf Christine C Davari Kathrin K Gallus Christian C Masri Joumana J Mufazalov Ilgiz A IA Neurath Markus F MF Wunderlich F Thomas FT Schattenberg Jörn M JM Galle Peter R PR Weigmann Benno B Waisman Ari A Glasmacher Elke E Hövelmeyer Nadine N

Nature communications 20170428

Bcl-3 is an atypical NF-κB family member that regulates NF-κB-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear. Here we show that Bcl-3 expression levels in colonic T cells correlate with disease manifestation in patients with inflammatory bowel disease. Mice with T-cell-specific overexpression of Bcl-3 develop severe colitis that can be attributed to defective Treg cell development and function, leading to the inf ...[more]

PMID: 28452361

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Project description:Background and Aims: We have shown in several controlled rat and human infection studies that dietary calcium improves intestinal resistance and strengthens the mucosal barrier. Reinforcement of gut barrier function is also relevant for inflammatory bowel disease (IBD). Therefore, we investigated the effect of supplemental calcium on spontaneous colitis development in HLA-B27 transgenic rats, an experimental animal model of IBD. Methods: HLA-B27 transgenic rats were fed a purified high-fat diet containing either a low or high calcium content (30 and 120 mmol CaHPO4/kg diet, respectively) for almost 7 weeks. Inert chromium ethylenediamine-tetraacetic acid (CrEDTA) was added to the diets to quantify intestinal permeability by measuring urinary CrEDTA excretion. Relative fecal dry-weight was determined to quantify diarrhea. Colonic inflammation was determined histologically, and by measuring mucosal interleukin-1M-NM-2. In addition, colonic mucosal gene expression of individual rats was analyzed, using whole genome microarrays. Interesting results were verified by Q-PCR. Results: The high-calcium diet significantly prevented the increase in intestinal permeability and diarrhea with time in HLA-B27 rats developing colitis as compared to the low-calcium group. The histological colitis score and mucosal interleukin-1M-NM-2 levels were lower in high-calcium fed rats. Supplemental calcium prevented the colitis-induced increase in the expression of extracellular matrix remodeling genes (e.g. matrix metalloproteinases, procollagens and fibronectin), which was confirmed by Q-PCR. Conclusions: Dietary calcium inhibits colitis development in HLA-B27 transgenic rats. Calcium prevents the colitis-related increase in intestinal permeability, diminishes diarrhea, and lowers the inflammatory response in the mucosa, resulting in less extracellular matrix breakdown. Keywords: nutritional intervention Female HLA-B27/M-NM-22-microglobulin transgenic rats on an inbred Fisher 344 background (n=8 in experimental group and n=9 in control group) (Taconic Farms, Inc, Germantown, NY), 8-10 weeks old and with a mean body weight of 128 g at the start of the experiment, were housed individually in metabolic cages. Animals were kept in a temperature- and humidity-controlled environment and in a 12-h light-dark cycle. Rats were fed a purified M-bM-^@M-^XhumanizedM-bM-^@M-^Y Western diet which contained in the control situation (per kg): 200 g acid casein, 326 g corn starch, 174 g glucose, 160 g palm oil, 40 g corn oil, 50 g cellulose and 5.16 g CaHPO4.2H2O (corresponding to 30 mmol calcium/kg diet; Sigma-Aldrich, St Louis, MO). Vitamins and minerals (other than calcium) were added to all diets according to the recommendations of the American Institute of Nutrition 1993.17 The experimental diet contained more calcium (120 mmol calcium/kg diet) at the expense of glucose. All samples were individually labelled and hybridized (Cy5). Equal amounts of Cy3 cRNA of all animals were pooled to serve as standard reference pool.

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Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis.

Publications

Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis.

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