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The role of Interleukin-1 associated kinase 1 in intestinal inflammation

Interleukin-1相关激酶1在肠道炎症中的作用

基本信息

批准号：
252441188
负责人：
Professorin Dr. Anne Krug
金额：
--
依托单位：
Forschungsbereich Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/252441188?language=en
关键词：
role Interleukin associated kinase intestinal

项目摘要

In inflammatory bowel diseases (IBD) intestinal inflammation is thought to be due to a dysregulated immune response to commensal bacteria due to a defective epithelial barrier function, which leads to overstimulation of epithelial cells, dendritic cells (DCs) and macrophages in the underlying lamina propria. Activated DCs present luminal antigens and promote the expansion and differentiation of proinflammatory effector T helper (Th)1 and Th17 cells while inhibiting regulatory T cell (Treg) generation. The resulting shift in the balance of regulatory to effector Th cells sustains the chronic inflammatory response. Interleukin-1 receptor associated kinases (IRAKs) are critically involved in signal transduction downstream of Toll-like receptors (TLRs) and the IL-1 receptor. Interaction of phosphorylated IRAK1 with tumor necrosis factor receptor associated factor 6 leads to the activation of nuclear factor k B (NFkB) and mitogen activated protein kinases. IRAK1 deficiency leads to a reduced but not abrogated inflammatory cytokine response to TLR and IL-1R triggering, but IRAK1 is not essential for antimicrobial defense making it a safe target for inhibition. Recent evidence support an important role of IRAK1 for autoimmune and inflammatory diseases.Our hypothesis is that IRAK1 is critically involved in the pathogenesis of intestinal inflammation in IBD and may be an attractive novel target for therapy. This hypothesis is supported by our preliminary results obtained with IRAK1-deficient mice in two inducible colitis models which demonstrate a non-redundant role of IRAK1 in the development of intestinal inflammation. It is not well understood how IRAK1 signaling in the different immune and non-immune cell types in the intestinal mucosa contributes to inflammation. Our results so far suggest that IRAK1 signaling in T cells plays a dominant role in colitis development, but also show a significant contribution of IRAK1 signaling in non-T cells, including innate immune cells and epithelial cells. In the proposed project we will therefore investigate: 1) the specific function of IRAK1 signaling in T cells and non-T cells for effector Th cell and Treg generation and intestinal accumulation during colitis, 2) the contribution of IRAK1 signaling in intestinal epithelial cells to colitis development, 3) the efficacy of an IRAK1/4 inhibitor in murine experimental colitis and 4) the expression of IRAK1 in intestinal mucosa of IBD patients as well as the role of IRAK1 for human Th cell differentiation.

在炎症性肠病（IBD）中，肠道炎症被认为是由于上皮屏障功能缺陷导致对肠道细菌的免疫应答失调，这导致上皮细胞、树突状细胞（DC）和巨噬细胞在下层固有层中的过度刺激。活化的DC呈递管腔抗原并促进促炎效应T辅助细胞（Th）1和Th 17细胞的扩增和分化，同时抑制调节性T细胞（Treg）的产生。调节性Th细胞与效应性Th细胞的平衡的改变维持了慢性炎症反应。白细胞介素-1受体相关激酶（IRAK）在Toll样受体（TLR）和IL-1受体下游的信号转导中起关键作用。磷酸化IRAK 1与肿瘤坏死因子受体相关因子6的相互作用导致核因子k B（NF k B）和促分裂原活化蛋白激酶的活化。IRAK 1缺陷导致对TLR和IL-1 R触发的炎性细胞因子应答减少但不消除，但IRAK 1对于抗菌防御不是必需的，使其成为安全的抑制靶标。最近的证据支持IRAK 1在自身免疫性疾病和炎症性疾病中的重要作用，我们的假设是IRAK 1在IBD的肠道炎症的发病机制中起关键作用，并且可能是一个有吸引力的新的治疗靶点。这一假设得到了我们在两种诱导性结肠炎模型中用IRAK 1缺陷小鼠获得的初步结果的支持，这些模型证明了IRAK 1在肠道炎症发展中的非冗余作用。目前尚不清楚肠粘膜中不同免疫和非免疫细胞类型中的IRAK 1信号传导如何导致炎症。到目前为止，我们的研究结果表明，T细胞中的IRAK 1信号传导在结肠炎的发展中起着主导作用，但也显示了IRAK 1信号传导在非T细胞中的重要作用，包括先天免疫细胞和上皮细胞。因此，在拟议项目中，我们将调查：1）IRAK 1信号传导在T细胞和非T细胞中对于效应Th细胞和Treg产生和结肠炎期间的肠积累的特异性功能，2）IRAK 1信号传导在肠上皮细胞中对结肠炎发展的贡献，3）IRAK 1/4抑制剂在鼠实验性结肠炎中的功效和4）IRAK 1在IBD患者的肠粘膜中的表达以及IRAK 1对于人Th细胞分化的作用。