Mechanisms associated with flares and remission in colitis

总结 炎症性肠病（IBD）影响全世界数百万人，并且其发病率正在增加。两 遗传和环境因素似乎在IBD发展中起作用。人类基因研究 将白细胞介素-23（IL-23）信号通路与IBD联系起来，但导致疾病的环境因素， 仍然难以捉摸世界范围内IBD发病率的上升与饮食西方化有关， 然而，在发展中国家，几乎没有科学证据支持因果关系。本申请中 我们将研究一组特殊的食品添加剂，即食品着色剂，对发展 结肠炎我们现在已经发现，食品着色剂红40，也被称为诱惑红AC，促进结肠炎 在条件性表达低水平IL-23的小鼠（称为R23 FR小鼠）中，但在野生型小鼠中不存在。红色 40是世界上最丰富的食用色素，年产量超过230万公斤。人们普遍 用于软饮料、樱桃味产品、糖果、乳制品、药品和化妆品中的红色着色剂。有趣的是， 含有红色40的饮料，Kool-Aid和保湿溶液Pedialyte Cherry也会导致结肠炎， R23 FR小鼠。R23 FR小鼠中Red 40诱导的结肠炎需要微生物群和CD 4 + T细胞。基于这些 和其他结果在这里提出，我们制定了一个中心假设，红40或其代谢物半抗原化 在野生型小鼠中产生耐受性的细菌或内源性蛋白，或在其中IL-23 表达失调。我们将在本提案中研究涉及生成和预防的机制 这些反应。具体来说，我们将定义：1）如果红色40及其代谢产物ANSA是半抗原; 2）如何红色 如果Red 40或ANSA特异性T细胞在R23 FR小鼠中产生，

Summary Inflammatory bowel diseases (IBD) affect millions of individuals worldwide and its incidence is increasing. Both genetic and environmental factors appear to play a role in IBD development. Genetic studies in humans have linked the interleukin-23 (IL-23) signaling pathway with IBD, but the environmental factors contributing to disease, have remained elusive. The rising incidence of worldwide IBD has been associated with westernization of dietary habits in developing countries, however there is little scientific evidence to support causality. In this application we will examine the role of a particular group of dietary additives, namely food colorants, to development of colitis. We have now discovered that the food colorant Red 40, also known as Allura Red AC, promotes colitis in mice that conditionally express low levels of IL-23 (referred to as R23FR mice), but not in wild type mice. Red 40 is the most abundant food colorant in the world, with annual production exceeding 2.3 million kg. It is widely used in as red colorant in soft drinks, cherry flavored products, candy, dairy, drugs, and cosmetics. Of interest, the Red 40-containing beverages, Kool-Aid and the hydrating solution Pedialyte Cherry can also cause colitis in R23FR mice. Red 40-induced colitis in R23FR mice requires the microbiota and CD4+ T cells. Based on these and other results presented here, we formulate a central hypothesis that the Red 40 or its metabolites haptenize bacterial or endogenous proteins to generate tolerance in wild type mice, or colitis in mice in which IL-23 expression is dysregulated. We will study in this proposal the mechanisms involved in generation and prevention of these responses. Specifically, we will define: 1) if Red 40 and its metabolite ANSA are haptens; 2) how Red 40 induces tolerance in control mice; and 3) if Red 40 or ANSA-specific T cells are generated in R23FR mice