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，由遗传易感个体的多因素病症引起。最近从人类全基因组关联研究和小鼠 IBD 模型中积累的数据表明，白细胞介素 22 (IL-22) 通路是 IBD 治疗的有希望的候选者。该项目的总体目标是提供一种新的干预措施，以安全地增强 IL-22 对 IBD（特别是 UC）治疗的有益作用。为了实现目标，我们需要将注意力集中在 事实上，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 和作为 IL-22 内源性抑制剂的 IL-22 结合蛋白 (IL-22BP)。事实上，我们之前证明 IL-22BP 的过度表达会损害葡聚糖硫酸钠 (DSS) 诱导的急性结肠炎的恢复。然而，目前在包括 IBD 在内的任何研究领域中，有关 IL-22BP 的信息很少。我们的初步研究发现，IL-22BP 在正常结肠中高表达，并且这种表达水平在炎症尤其是 Th1 介导的炎症中降低。出乎意料的是，我们发现正常结肠内存在大量未成熟的NK细胞，它们可以产生IL-22BP。相反，当IL-22BP表达变得不可检测时，炎症导致NK细胞进一步成熟。我们之前证明 IL-22 刺激上皮细胞产生粘蛋白 1 (Muc1)，这是肠粘液的主要成分。有趣的是，我们最近发现 Muc1 有助于抑制 Th17 反应，该反应已被证明会引发 IL-22 的炎症功能，而不是保护功能。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到 IL-22BP 的负控制，IL-22BP 抑制 Muc1 介导的 Th17 反应抑制，并且主要确定 IL-22BP 的结肠表达水平通过传统 NK 细胞的成熟状态。在这方面，本项目将测试IL-22BP的缺乏是否可以改善Th2介导的慢性结肠炎（目标1.1），IL-22BP拮抗剂是否对该结肠炎具有治疗潜力（目标1.1），治疗效果是否可以稳定不同的细胞因子环境（目标 1.2）、IL-22BP 如何在正常结肠中持续表达（目标 2.1）、IL-22BP 表达如何在不同条件下减少肠道炎症状况（目标 2.2），以及如何进一步修改降低水平（目标 2.2）。