IL-22 pathway in IBD

描述(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疾病引起。最近，来自人类全基因组关联研究和小鼠IBD模型的数据积累，强调了白介素22(IL-22)途径是治疗IBD的一个有前途的候选途径。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治疗IBD特别是UC的有益效果。为了实现这一目标，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，如IL-17和作为IL-22的内源性抑制物的IL-22结合蛋白(IL-22BP)。事实上，我们以前已经证明，IL-22BP的过度表达损害了葡聚糖硫酸钠(DSS)诱导的急性结肠炎的恢复。然而，目前在任何研究领域，包括IBD，关于IL-22BP的信息都很少。我们的初步研究发现，IL-22BP在正常结肠中高表达，在炎症尤其是Th1介导的炎症背景下，IL-22BP的表达水平降低。出乎意料的是，我们发现正常结肠中存在大量未成熟的NK细胞，它们可以产生IL-22BP。相反，当检测不到IL-22BP表达时，炎症导致NK细胞进一步成熟。我们先前证明了IL-22刺激上皮细胞产生粘蛋白1(MUC1)，粘蛋白1是肠道粘液的主要成分。有趣的是，我们最近发现，MUC1有助于抑制Th17反应，而Th17反应被证明是诱导IL-22的炎症功能，而不是保护功能。根据这些数据，我们假设IL-22在Th2介导的慢性结肠炎中的有益作用是由IL-22BP负向控制的，IL-22BP抑制了MUC1介导的Th17反应，而IL-22BP在结肠的表达水平主要由常规NK细胞的成熟状态决定。在这方面，这个项目将测试缺乏IL-22BP是否可以改善Th2介导的慢性结肠炎(AIM 1.1)，IL-22BP拮抗剂是否对这种结肠炎有治疗潜力(AIM 1.1)，如果治疗效果在不同的细胞因子环境中可以稳定(AIM 1.2)，IL-22BP在正常结肠中如何结构性表达(AIM 2.1)，IL-22BP在肠道炎症条件下的表达如何减少(AIM 2.2)，以及降低的水平如何进一步修改(AIM 2.2)。

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).