THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE

干扰素共有序列结合蛋白（ICSBP/IRF-8）属于干扰素家族， 转录因子的调节因子家族是Thl免疫应答所必需的。 ICSBP在宿主防御微生物病原体中起着重要作用，但确切的ICSBP是一种特异性的蛋白质。 ICSBP在炎症和慢性炎症性疾病中的作用尚不清楚。IL-10-/- 发生以Th 1细胞因子增加为特征的结肠炎的小鼠，模拟了 人克罗恩病（CD）。显示了ICSBP在结肠炎发展中的重要性 ICSBP和IL-10双敲除小鼠没有患病。此外，ICSBP mRNA 和蛋白在IL-10-/-小鼠结肠炎的结肠中高度表达， ICSBP/IL-10双敲除小鼠IL-12和iNOS的表达显著降低。一致 根据这些结果，CD患者的ICSBP表达显著高于正常人 个体ICSBP在几个位点都有活性。ICSBP在TLR 4途径中与TRAF 6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 它被蛋白酶体降解。探讨ICSBP作为治疗CD的合适靶点， 本建议围绕三个目标展开：1）我们将分析ICSBP的监管 在用各种TLR和NOD 2配体活化的巨噬细胞和树突细胞中表达。 此外，我们将定义ICSBP在调节性T细胞生成中的作用。2)我们将 明确Cbl在Thl免疫应答调控中的作用，分析Cbl在Thl免疫应答调控中的作用， Cbl在结肠炎发展中的作用。3)我们将确定TLR 4的治疗作用， 小鼠结肠炎模型中细胞渗透性肽试剂的体内ICSBP抑制。这些 研究将促进我们对ICSBP在粘膜免疫应答中的作用的理解， ICSBP可能成为CD治疗的新靶点。

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.