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 调节因子家族的转录因子，是Th1免疫反应所必需的。 ICSBP在宿主抵御微生物病原体方面起着重要作用，但确切的 ICSBP在炎症和慢性炎症性疾病中的作用尚不清楚。IL-10-/- 患有结肠炎的小鼠，其特征是Th1细胞因子增加，在许多方面模仿 人类克罗恩病(CD)。ICSBP在结肠炎发生发展中的重要性 在ICSBP和IL-10双基因敲除小鼠中缺乏疾病。此外，ICSBP mRNA 和蛋白在IL-10-/-结肠炎小鼠的结肠中高表达，而表达 IL-12和iNOS在ICSBP/IL-10双重KO小鼠中的表达显著降低。在协议中 根据这些结果，CD患者ICSBP的表达明显高于正常 个人。ICSBP在多个基因座上表现活跃。ICSBP通过TLR4途径与TRAF6相互作用， 并与iNOS和IL-12p40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Cb1泛素化，导致 它被蛋白酶体降解。为了探索ICSBP作为CD治疗的合适靶点， 这项建议围绕三个目标构建：1)我们将分析ICSBP的监管 不同TLR和NOD2配体激活的巨噬细胞和树突状细胞的表达。 此外，我们还将确定ICSBP在调节性T细胞生成中的作用。2)我们会 明确Cb1在Th1免疫应答调控中的作用 Cbl在结肠炎发生发展中的作用我们将确定TLR4和TLR4的治疗效果 细胞通透性多肽试剂对小鼠结肠炎模型ICSBP的体内抑制作用。这些 研究将促进我们对ICSBP在粘膜免疫反应中的作用的理解， 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.