Macrophage Gene Expression in Mucosal Inflammation

本申请中提出的实验将探索巨噬细胞激活在发病机制中的作用。 炎症性肠病(IBD)。我们将重点研究IL-12p40在血管内皮细胞中的分子调控 巨噬细胞在T辅助细胞(Th1)介导的慢性疾病中的重要生物学意义 发炎。我们最近描述了IL-12 p40启动子中的一个新的复合元件 与活化T细胞核因子(NFAT)和干扰素调节因子(IRF)成员相互作用 转录因子家族。这个调控元件参与了IL-12 p40的协同诱导 细菌产物和干扰素-γ的启动子活性，是抑制IL-γ的重要靶点。 12 p40基因通过多种信号转导途径表达。 这项建议的总体目标是了解IL-12p40在实验中的分子调控。 IBD模型的建立。实验将阐明两个新发现的抗炎信号的作用 巨噬细胞中的转导途径：血红素加氧酶-1和磷脂酰肌醇-3-激酶 (PI3K)。我们假设这些抗炎途径通过调节NFAT/IRF而汇聚。 IL-12 p40启动子的相互作用。通过抑制IL-12p40、HO-1和PI3K起到分子“刹车”作用 巨噬细胞激活，这可能限制慢性肠炎的程度和持续时间。 白介素12(IL-12)是一种炎性蛋白，已被证明在脑出血中起重要作用。 人类克罗恩病(CD)的进展。在本应用程序中，我们将测试治疗性干预 小鼠模型的CD能抑制免疫系统中称为巨噬细胞的细胞产生IL-12。研究 将为我们提供有关可能存在缺陷的免疫抑制途径的重要信息 并可能导致针对巨噬细胞和IL-1的新的治疗措施。 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.