IL-22 pathway in IBD

IBD 中的 IL-22 通路

• 批准号: 8591390
• 负责人: EMIKO MIZOGUCHI
• 金额: $ 35.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591390
• 关键词: Acute; Applications Grants; Attenuated; Binding Proteins; Binding Sites; Cell Differentiation process; Cell Maturation; Chronic; Colitis; Colon; Crohn' s disease; Data; Dependence; Disease; Disease model; Enteral; Environment; Epithelial Cells; Exhibits; Experimental Models; Genes; Genetic; Goals; Human Genetics; Human Genome; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-17; Intervention; Intestinal Diseases; Intestines; Mediating; Membrane; Mucin 1 protein; Mucin-1 Staining Method; Mucins; Mucous body substance; Mus; Natural Killer Cells; Pathogenesis; Pathway interactions; Patients; Recovery; Reporting; Research; STAT3 gene; Sodium Dextran Sulfate; Staging; Study models; Testing; Therapeutic; Therapeutic Effect; Ulcerative Colitis; base; cytokine; design; directed attention; genome wide association study; improved; inhibitor/antagonist; interleukin-22; microorganism; novel; novel therapeutics; overexpression; promoter; protective effect; protein expression; public health relevance; response

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic intestinal disorder that is caused by multi-factorial conditions in genetically predisposed individuals. Recently accumulating data from human genome-wide association studies and mouse IBD models have highlighted interleukin-22 (IL-22) pathway as a promising candidate for IBD therapy. The overall objective of this project is to provide a novel intervention to safely enhance the beneficial effect of IL-22 for treatment of IBD particularly UC. In order to achieve the goal, we need to direct an attention to a fact that functions of IL-22 are determined not only by its expression level but also by other factors such as IL-17 and IL-22- binding protein (IL-22BP) that serves as an endogenous inhibitor of IL-22. Indeed, we demonstrated previously that overexpression of IL-22BP impaired the recovery from acute colitis induced by dextran sodium sulfate (DSS). However, only little information is currently available on the IL-22BP in any research fields, including IBD. Our preliminary study found that IL-22BP was highly expressed in normal colon, and this expression level was reduced in the context of inflammation particularly Th1-mediated inflammation. Unexpectedly, we have found that large proportion of immature NK cells exist in the normal colon and they can produce IL-22BP. In contrast, inflammation led to the further maturation of NK cells when IL-22BP expression became undetectable. We demonstrated previously that IL-22 stimulates epithelial cells to produce a mucin 1 (Muc1), a major component in intestinal mucus. Interestingly, we have recently found that the Muc1 contributes to the suppression of Th17 response that has been shown to elicit inflammatory, rather than protective, function of IL-22. Based on these data, we hypothesize that beneficial function of IL- 22 in Th2-mediated chronic colitis is controlled negatively by IL-22BP that suppresses the Muc1-mediated inhibition of Th17 responses, and the colonic expression levels of IL-22BP are determined primarily by the maturation status of conventional NK cells. In this regard, this project will test if absence o IL-22BP improves Th2-mediated chronic colitis (Aim 1.1), whether IL-22BP-anatagonist has therapeutic potential in this colitis (Aim 1.1), if the therapeutic effect can be stable in differet cytokine environments (Aim 1.2), how IL-22BP is constitutively expressed in normal colon (Aim 2.1), how IL-22BP expression is reduced under intestinal inflammatory condition (Aim 2.2), and how the reduction levels are further modified (Aim 2.2).

描述（由申请人提供）：炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC），是一种慢性肠道疾病，是由遗传性倾向的个体中多因素疾病引起的。最近，来自人类基因组关联研究和小鼠IBD模型的数据突出了白介素22（IL-22）途径，作为IBD治疗的有前途的候选人。该项目的总体目的是提供一种新颖的干预措施，以安全地增强IL-22对IBD尤其是UC治疗的有益效果。为了实现目标，我们需要将注意力引向 事实认为，IL-22的功能不仅取决于其表达水平，还取决于其他因素，例如IL-17和IL-22-结合蛋白（IL-22BP），它是IL-22的内源性抑制剂。确实，我们以前证明了IL-22bp的过表达损害了硫酸葡萄糖钠（DSS）诱导的急性结肠炎的恢复。但是，当前在包括IBD在内的任何研究领域的IL-22BP上只有很少的信息。我们的初步研究发现，IL-22bp在正常结肠中高度表达，并且在炎症的背景下，该表达水平降低了，尤其是Th1介导的炎症。出乎意料的是，我们发现正常结肠中存在很大一部分未成熟的NK细胞，并且可以产生IL-22bp。相反，当IL-22bp表达变得无法检测时，炎症导致NK细胞进一步成熟。我们先前证明IL-22刺激上皮细胞以产生粘蛋白1（MUC1），这是肠粘膜中的主要成分。有趣的是，我们最近发现，MUC1有助于抑制Th17反应，该反应引起了IL-22的炎症而不是保护性的功能。基于这些数据，我们假设IL-22在Th2介导的慢性结肠炎中的有益功能受IL-22BP的负面控制，IL-22BP抑制了MUC1介导的Th17反应的抑制作用，而IL-22BP的结肠表达水平主要通过常规NK细胞的成熟状态确定。在这方面，该项目将测试是否缺乏IL-22BP是否改善了Th2介导的慢性结肠炎（AIM 1.1），是否在该结肠炎中具有治疗潜力（AIM 1.1），是否可以在差异细胞因子环境中稳定（AIM 1.2），IL-22BP在差异中稳定（目标1.1）在肠道炎症条件下（AIM 2.2）以及如何进一步修饰了IL-22bp的表达（AIM 2.2）（AIM 2.2）。