Regulatory Role of TNFR1 in Inflammatory Bowel Disease

描述(由申请人提供)： 炎症性肠病(IBD)是一组影响个体一生的慢性炎症性疾病。克罗恩病(CD)和溃疡性结肠炎(UD)都被认为是自身免疫性疾病，结肠上皮细胞(CEC)和固有层(LP)细胞可能在IBD的发展过程中发挥关键作用。然而，这两个群体在IBD发病机制中的确切作用，或者在IBD的调节中的确切机制，仍然不清楚。我们以前已经发现肿瘤坏死因子受体I型(TNFR1)和II型(TNFR2)在CEC中表达：TNFR1是结构性表达，而TNFR2是在炎症条件下诱导表达的。TNFR2在CEC上的诱导与结肠的增殖和增殖密切相关。我们最近的初步研究也证实，表达在LP细胞中的非淋巴样、髓系细胞(最可能是树突状细胞和巨噬细胞)上的TNFR1是诱导LP细胞凋亡的天然免疫反应的关键调节因子。令人兴奋的是，这种由TNFR1介导的对先天性免疫反应的调节通过激活MAPK途径促进了CEC的重建。这些发现为我们提供了一个更密切地研究CEC和非淋巴样LP细胞中TNFR1和TNFR2在结肠炎发病机制中的作用的大好机会。根据我们的初步研究，我们假设TNFR1在人类IBD的调节中发挥关键作用。在目标I中，我们计划检测TNFR1对TNFR2介导的CEC和巨噬细胞信号级联反应的抑制作用：将TNFR1和/或TNFR2结构性或人工过表达的细胞株与两种不同的TNFR配体--肿瘤坏死因子和淋巴毒素连接后，检测其抑制作用。在AIM II中，我们将研究几丁质酶3-样-1(CHI3L1)在结肠炎急性期和随后的恢复期中可能负向调节TNFR1信号的作用。基因芯片分析初步发现CHI3L1基因可能参与IBD的发病机制。这些研究将有助于阐明在肠道炎症情况下，TNFR1介导的CEC激活在这类配体中的独特调节作用。我们相信，从这项研究中获得的数据将为开发与肿瘤坏死因子相关的新的人类IBD治疗方法提供重要的理论基础。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions that affects individuals throughout their life. Both Crohn's disease (CD) and ulcerative colitis (UD) are thought of as autoimmune diseases, and colonic epithelial cells (CEC) and underlying lamina propria (LP) cells may play a critical role during the development of IBD. However, the exact mechanistic role of these two populations in the pathogenesis, or alternatively in the regulation of IBD, is still unclear. We have previously identified that tumor necrosis factor receptor -type I (TNFR1) and -type II (TNFR2) are expressed by CEC: TNFR1 is constitutively expressed whereas TNFR2 expression is induced under inflammatory conditions. The induction of TNFR2 on CEC is closely associated with colonic proliferation and hyperplasia. Our recent preliminary studies have also identified that the TNFR1 expressed on non-lymphoid, myeloid lineage cells (most likely dendritic cells and macrophages) present in LP cells is a critical regulator of innate immune responses by inducing apoptosis in LP cells. Excitingly, this TNFR1-mediated regulation of innate immune responses contributes to the initiating CEC restitution through the MAPK pathway activation. These discoveries provide us with a great opportunity to more closely examine the role of TNFR1 and TNFR2 in CEC and non-lymphoid LP cells in the pathogenesis of colitis. Based on our preliminary studies, we hypothesize that TNFR1 plays a critical role in the regulation of human IBD. In Aim I, we plan to examine the suppressive role of TNFR1 against TNFR2 mediated signaling cascade on CEC and macrophages: the effect will be examined by using cell lines which TNFR1 and/or TNFR2 are constitutively or artificially overexpressed or knocked-down after ligated with two distinct TNFR ligands, TNF and Lymphotoxin. In Aim II, we will examine the role of Chitinase 3-like-1 (CHI3L1) that may negatively regulate the TNFR1 signalings during the acute and following recovery phase of colitis. The CHI3L1 had been initially picked up by DNA microarray analysis and this molecule may be actively involved in the pathogenesis of IBD. These studies will help clarify the distinct regulatory role of TNFR1-mediated activation of CEC in the type of ligands under intestinal inflammation. We believe the data obtained from this study would provide an important rationale to develop new TNF related therapeutic approaches for human IBD.