MACROPHAGE GENE EXPRESSION IN MUCOSAL INFLAMMATION

超出提供的空间。本申请中提出的实验将探索巨噬细胞激活在炎症性肠病(IBD)发病机制中的作用。我们将集中于巨噬细胞中IL-12p40的分子调控，这是T辅助细胞(THL)介导的慢性炎症中最有生物学意义的事件之一。我们最近描述了IL-12p40启动子中的一个新的复合元件，它与激活的T细胞核因子(NFAT)和干扰素调节因子(IRF)转录因子家族的成员相互作用。该调控元件参与了细菌产物和干扰素-γ对IL-12p40启动子活性的协同诱导，是通过多种信号转导途径抑制IL-12p40基因表达的重要靶点。这项建议的总体目标是了解IL-12p40在IBD实验模型中的分子调控。实验将阐明两个新发现的抗炎信号转导通路在巨噬细胞中的作用：血红素加氧酶-1(HO-1)和磷脂酰肌醇-3-激酶(PI3K)。我们假设这些抗炎途径通过调节IL-12p40启动子上的NFAT/IRF相互作用而汇聚。通过抑制IL-12p40，HO-1和PI3K作为巨噬细胞激活的分子“刹车”，可能限制慢性肠道炎症的程度和持续时间。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. 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 (Thl)-mediated chronic inflammation. We have recently described a novel composite element in the IL-12p40 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. PERFORMANCE SITE ========================================Section End===========================================