IL-22 pathway in IBD

描述（由申请方提供）：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条件引起。近年来，人类全基因组关联研究和小鼠IBD模型的数据显示，白细胞介素-22（IL-22）通路是IBD治疗的一个有希望的候选途径。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的有益作用。为了实现目标，我们需要把注意力集中在 事实上，IL-22的功能不仅由其表达水平决定，还由其他因素如IL-17和IL-22结合蛋白（IL-22 BP）决定，IL-22结合蛋白（IL-22 BP）是IL-22的内源性抑制剂。事实上，我们先前证明IL-22 BP的过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，目前在包括IBD在内的任何研究领域中关于IL-22 BP的信息都很少。我们的初步研究发现，IL-22 BP在正常结肠中高度表达，并且在炎症尤其是Th 1介导的炎症的背景下，这种表达水平降低。出乎意料的是，我们发现大部分未成熟的NK细胞存在于正常结肠中，并且它们可以产生IL-22 BP。相反，当IL-22 BP表达变得不可检测时，炎症导致NK细胞的进一步成熟。我们以前证明，IL-22刺激上皮细胞产生粘蛋白1（Muc 1），这是肠粘液的主要成分。有趣的是，我们最近发现，Muc 1有助于抑制Th 17反应，这已被证明是引发炎症，而不是保护，IL-22的功能。基于这些数据，我们假设IL- 22在Th 2介导的慢性结肠炎中的有益功能由IL-22 BP负向控制，IL-22 BP抑制Muc 1介导的对Th 17应答的抑制，并且IL-22 BP的结肠表达水平主要由常规NK细胞的成熟状态决定。在这方面，本项目将测试IL-22 BP的缺乏是否改善Th 2介导的慢性结肠炎（目的1.1），IL-22 BP-拮抗剂是否具有治疗结肠炎的潜力（目的1.1），如果治疗效果可以在非细胞因子环境中稳定，（目的1.2）IL-22 BP在正常结肠中的组成性表达（目的2.1），IL-22 BP表达在肠道炎症条件下如何降低（目标2.2），以及如何进一步修改削减水平（目标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).