Macrophage Gene Expression in Mucosal Inflammation

本申请中提出的实验将探索巨噬细胞活化在发病机制中的作用 炎症性肠病（IBD）我们将重点关注IL-12 p40在肿瘤细胞中的分子调控。 巨噬细胞作为T辅助细胞1（Th 1）介导的慢性炎症中最具生物学意义的事件之一， 炎症我们最近描述了IL-12 p40启动子中的一种新的复合元件， 与活化T细胞核因子（NFAT）和干扰素调节因子（IRF）的成员相互作用 转录因子家族。该控制元件参与IL-12 p40的协同诱导 启动子活性的细菌产物和干扰素-γ（IFN-γ），是一个重要的目标，为抑制IL- 12 p40基因表达通过多种信号转导途径。 本提案的总体目标是了解IL-12 p40的分子调控， IBD模型实验将阐明两个新认识的抗炎信号的作用， 巨噬细胞中的转导途径：血红素加氧酶-1（HO-1）和磷脂酰肌醇-3-激酶 （PI3K）。我们假设这些抗炎通路通过调节NFAT/IRF而汇聚在一起。 在IL-12 p40启动子处的相互作用。通过抑制IL-12 p40，HO-1和PI 3 K充当分子“刹车” 巨噬细胞活化，可能限制慢性肠道炎症的程度和持续时间。 白细胞介素-12（IL-12）是一种炎性蛋白，已被证明在炎症反应中是重要的。 人克罗恩病（CD）的进展。在本申请中，我们将测试治疗干预措施， CD小鼠模型，以抑制称为巨噬细胞的免疫系统细胞产生IL-12。研究 将为我们提供有关免疫抑制途径的重要信息， 并可能导致靶向巨噬细胞和IL-2的人IBD中的新的治疗干预。 12.

Experiments proposed in this application will explore the role of macrophage activation in the pathogenesis of the inflammatory bowel diseases (IBD). We will focus on the molecular regulation of IL-12 p40 in macrophages as one of the most biologically significant events in T-helper1 (Th1)-mediated chronic inflammation. We have recently described a novel composite element in the IL-12 p40 promoter that interacts with members of the nuclear factor of activated T cells (NFAT) and interferon regulatory factor (IRF) families of transcription factors. This control element is involved in the synergistic induction of IL-12 p40 promoter activity by bacterial products and interferon-y (IFN-y), and is an important target for inhibition of IL- 12 p40 gene expression through several signal transduction pathways. The overall goal of this proposal is to understand the molecular regulation of IL-12 p40 in experimental models of IBD. Experiments will elucidate the role of two newly appreciated anti-inflammatory signal transduction pathways in macrophages: Heme oxygenase-1 (HO-1) and phosphatidylinositol-3-kinase (PI3K). We hypothesize that these anti-inflammatory pathways converge through regulation of NFAT/IRF interactions at the IL-12 p40 promoter. By inhibiting IL-12 p40, HO-1 and PI3K serve as molecular "brakes" for macrophage activation that may limit the extent and duration of chronic intestinal inflammation. lnterleukin-12 (IL-12) is an inflammatory protein that has been demonstrated to be important in the progression of human Crohn's disease (CD). In this application, we will test therapeutic interventions in mouse models of CD to inhibit IL-12 production by cells of the immune system called macrophages. Studies in this application will give us important information about immune inhibitory pathways that may be defective in human IBD and may lead to new therapeutic interventions in human IBD that target macrophages and IL- 12.