Inhibition of Microflora-Induced Colitis by NF-kB

描述（由申请人提供）：本申请的目的是描述NF-(B)亚基在炎症性肠病发展中的作用。NF-(B)是一个由5个亚基组成的转录因子家族。响应toll样受体（TLR）信号的NF-(B)激活在驱动炎性肠病特征的病理性炎症中起核心作用。然而，研究表明，除了促炎作用外，单个亚单位也可能具有意想不到的抗炎作用。缺乏NF- B的p50/p105亚基的小鼠对结肠炎的发展敏感，至少部分原因是先天免疫系统的造血细胞缺陷导致IL-12 p40的过量产生。相反，缺乏NF-（B亚单位c-Rel）的小鼠对结肠炎有抵抗力，并且IL-12 p40的表达降低。因此，NF-(B)家族成员p50/p105和c-Rel在调节下肠炎症中似乎具有相反的功能。该提案包含两个目标。目的1：确定il - 12p40在p50/p105缺陷巨噬细胞中表达增加的基础。我们发现，在缺乏p50/p105的巨噬细胞中，TLR诱导的IL-12 p40表达增加与干扰素-2 （IFN-2）分泌增加和STAT1激活增强有关。然而，IFN-2产生增加与il - 12p40表达增加之间的关系尚未明确。一种可能性是il - 12p40表达的增加是继发于IFN-2产生的增加和STAT1激活的增强。另一种可能性是，基于p50直接抑制IL-12 p40表达的能力，在p50缺失的巨噬细胞中观察到的IL-12 p40表达增加与IFN-2分泌无关。这个目的的目的是检查这些可能性和描绘p50的抑制功能。目的2：表征c-Rel在调节粘膜炎症反应中的作用。NF- B家族成员c-Rel在调节IL-23亚基p40和p19的诱导中起重要作用（11,12）。与c-Rel在体内调节IL-23表达的作用一致，我们发现先天免疫系统中缺乏c-Rel的小鼠对T细胞介导的结肠炎的发展具有抗性，并且表现出干扰素-3和IL-17的表达降低(8)。这导致我们假设先天免疫系统中c- Rel的存在对于诱导Th1和Th17介导的肠道病理是必要的。为此，我们打算利用体内结肠炎模型和体外培养系统，通过确定先天免疫系统中c-Rel的缺失如何干扰效应和调节性T细胞群的分化和激活，来评估这一假设。这些研究将促进我们对IBD的理解，并可能提出新的治疗方法。公共卫生相关性：NF-(B)是炎症性肠病病理特征的中心介质。对NF-(B)家族成员功能的详细了解可能会揭示新的治疗方法。

DESCRIPTION (provided by applicant): The purpose of this proposal is to delineate the role of NF-(B subunits in the development of inflammatory bowel disease. NF-(B is a transcription factor family consisting of 5 subunits. Activation of NF-(B in response to Toll-like receptor (TLR) signaling plays a central role in driving the pathological inflammation that characterizes inflammatory bowel disease. However, it has been shown that in addition to pro-inflammatory effects, individual subunits can have unexpected anti-inflammatory effects as well. Mice lacking the p50/p105 subunit of NF-(B are sensitized to the development of colitis, due at least in part to a defect within hematopoietic cells of the innate immune system that leads to excessive production of IL-12 p40. In contrast, mice lacking the NF-(B subunit c-Rel, are resistant to colitis, and have reduced expression of IL-12 p40. Thus, NF-(B family members p50/p105 and c-Rel appear to have opposing functions in the regulation of lower bowel inflammation. The proposal contains 2 aims. Aim 1: To determine the basis for increased expression of IL-12 p40 in p50/p105-deficient macrophages. We have found that increased TLR- induced expression of IL-12 p40 in macrophages that lack p50/p105 is associated with augmented secretion of interferon-2 (IFN-2) and enhanced activation of STAT1. However, the relationship between augmented production of IFN-2 and increased expression of IL-12 p40 has not been define. One possibility is that increased expression of IL-12 p40 is secondary to augmented production of IFN-2 and enhanced activation of STAT1. An alternative possibility is that increased expression of IL- 12 p40 observed in p50-deficient macrophages is independent of IFN-2 secretion, based on the direct ability of p50 to inhibit expression of IL-12 p40. The purpose of this aim is to examine these possibilities and delineate the inhibitory function of p50. Aim 2: To characterize the role of c-Rel in regulating the mucosal inflammatory response. The NF-(B family member c-Rel plays an essential role in regulating induction of both IL-23 subunits, p40 and p19 (11, 12). Consistent with a role for c- Rel in regulating IL-23 expression in vivo, we have found that mice lacking c-Rel within the innate immune system are resistant to the development of T cell-mediated colitis, and exhibit reduced expression of both interferon-3 and IL-17 (8). This has lead us to hypothesize that the presence of c- Rel within the innate immune system is necessary for induction of Th1 and Th17 mediated bowel pathology. In this aim, we intend to evaluate this hypothesis by determining how the absence of c-Rel within the innate immune system interferes with the differentiation and activation of effector and regulatory T cell populations using an in vivo colitis model and in vitro culture system. These studies will advance our understanding of IBD and possibly suggest novel therapeutic approaches. PUBLIC HEALTH RELEVANCE: NF-(B is a central mediator of the pathology that characterizes inflammatory bowel disease. A detailed understanding of the function of the NF-(B family members may unveil novel therapeutic approaches.