THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE

ICSBP 在粘膜免疫反应中的作用

• 批准号: 7141824
• 负责人: HUABAO XIONG
• 金额: $ 20.55万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141824
• 关键词: Crohn' s disease; binding proteins; biological signal transduction; colitis; dendritic cells; enzyme activity; gene expression; gene therapy; genetically modified animals; helper T lymphocyte; immune response; interferons; laboratory mouse; leukocyte activation /transformation; ligase; macrophage; mucosal immunity; polymerase chain reaction; protein degradation; protein protein interaction; protein structure function; therapy design /development; toll like receptor; transcription factor; western blottings

The IFN consensus sequence binding protein (ICSBP/IRF-8), which belongs to the interferon regulatory factor family of transcription factors, is essential for a Thl immune response. ICSBP plays an important role in the host defense against microbial pathogens, but the exact roles of ICSBP in inflammation and chronic inflammatory diseases are still not clear. IL-10-/- mice, which develop colitis characterized by increased Thl cytokines, mimic many aspects of human Crohn's disease (CD). The importance of ICSBP in the development of colitis is shown by the lack of disease in ICSBP and IL-10 double knockout mice. In addition, ICSBP mRNA and protein are highly expressed in the colons of IL-10-/- mice with colitis, while expression of IL-12 and iNOS is significantly compromised in ICSBP/IL-10 double KO mice. In agreement with these results, patients with CD have significantly higher ICSBP expression than normal individuals. ICSBP is active in several loci. ICSBP interacts with TRAF6 in the TLR4 pathway, and binds to ISRE sites in the iNOS and IL-12 p40 promoters, activating the expression of these genes. In addition, we find that ICSBP is ubiquitinated by the E3 ligase Cbl, resulting in its degradation by the proteasome. To expore ICSBP as a suitable target for therapy in CD, this proposal is structured around three aims: 1) We will analyze the regulation of ICSBP expression in macrophages and dendritic cells activated with various TLR and NOD2 ligands. In addition, we will define the role of ICSBP in the generation of regulatory T cells. 2) We will define the function of Cbl in the control of Thl immune immune response and analyze the role of Cbl in the development of colitis. 3) We will define the therapeutic effects of TLR4 and ICSBP inhibition by cell-permeable peptide reagent in vivo in murine colitis models. These studies will advance our understanding the role of ICSBP in the mucosal immune response, and may identify ICSBP as a new target for therapy in CD.

属于干扰素的IFN共有序列结合蛋白（ICSBP/IRF-8） 转录因子的调节因子家族对于THL免疫反应至关重要。 ICSBP在宿主防御微生物病原体中起着重要作用，但确切的 ICSBP在炎症和慢性炎症性疾病中的作用仍然不清楚。 IL-10 - / - 小鼠发展为以THL细胞因子升高为特征的结肠炎，模仿了许多方面 人克罗恩氏病（CD）。显示了ICSBP在结肠炎发展中的重要性 由于ICSBP和IL-10双基因敲除小鼠缺乏疾病。此外，ICSBP mRNA 和蛋白质在具有结肠炎的IL-10 - / - 小鼠的结肠中高度表达，而表达 在ICSBP/IL-10双KO小鼠中，IL-12和INOS的iL-12和iNOS被显着损害。同意 通过这些结果，CD患者的ICSBP表达明显高于正常 个人。 ICSBP在几个基因座中活跃。 ICSBP与TLR4途径中的TRAF6相互作用， 并与Inos和IL-12 p40启动子中的ISRE位点结合，激活 这些基因。此外，我们发现ICSBP被E3连接酶CBL泛素化，导致 蛋白酶体的降解。要将ICSBP视为CD治疗的合适靶标， 该提议围绕三个目的结构：1）我们将分析ICSBP的调节 用各种TLR和NOD2配体激活的巨噬细胞和树突状细胞中的表达。 此外，我们将定义ICSBP在调节T细胞产生中的作用。 2）我们会的 定义CBL在控制THL免疫反应中的功能并分析 CBL在结肠炎发展中的作用。 3）我们将定义TLR4和 在鼠结肠炎模型中，由细胞渗透肽试剂在体内抑制ICSBP。这些 研究将促进我们了解ICSBP在粘膜免疫反应中的作用， 并可以将ICSBP识别为CD治疗的新靶标。