MACROPHAGE GENE EXPRESSION IN MUCOSAL INFLAMMATION

超出所提供的空间。本申请中提出的实验将探索巨噬细胞活化在炎症性肠病（IBD）发病机制中的作用。我们将集中在巨噬细胞中IL-12 p40的分子调控作为T辅助细胞1（Thl）介导的慢性炎症中最具生物学意义的事件之一。我们最近描述了一种新的复合元件在IL-12 p40启动子，与活化T细胞的核因子（NFAT）和干扰素调节因子（IRF）家族的转录因子的成员相互作用。该控制元件参与细菌产物和干扰素-γ（IFN-γ）对IL-12 p40启动子活性的协同诱导，并且是通过几种信号转导途径抑制IL- 12 p40基因表达的重要靶标。本提案的总体目标是了解IBD实验模型中IL-12 p40的分子调控。实验将阐明两个新认识的抗炎信号转导途径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（PI 3 K）。我们假设这些抗炎途径通过调节IL-12 p40启动子处的NFAT/IRF相互作用而会聚。通过抑制IL-12 p40，HO-1和PI 3 K作为巨噬细胞活化的分子“刹车”，可以限制慢性肠道炎症的程度和持续时间。性能现场=

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===========================================