The complex formation of c-Kit and the IL-33R and its influence on SCF- and IL-33-induced mast cell effector functions

c-Kit和IL-33R复合物的形成及其对SCF和IL-33诱导的肥大细胞效应功能的影响

• 批准号: 392970554
• 负责人: Dr. Sebastian Drube
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392970554?language=en
• 关键词: complex; formation; Kit; IL; 33R

We identified a functionally relevant crosstalk between the activated receptor tyrosine kinase c-Kit and the IL-33R in mast cells. Thereby, activation of c-Kit by its ligand the stem cell factor (SCF) induces interaction of c-Kit with the IL-33R and potentiates the IL-33-induced cytokine production in mast cells. The interaction of activated c-Kit with the unligated IL-33R is not only the precondition for IL-33 to induce its full biological effector functions. Moreover the unligated IL-33R is also essential for activated c-Kit to mediate its complete signaling (e.g. Lyn and STAT activiation). Thererfore the unligated IL-33R establishes the basis for activated c-Kit to mediate SCF-induced and Lyn-dependent signaling pathways and effector functions in mast cells. However, the structural mechanism behind the formation of the c-Kit/IL-33R complex and its impact on SCF and/ or IL-33-induced mast cell effector functions in vitro and in vivo is unknown. Therefore, the overall goal of this study is to investigate the structural requirements for formation of the c-Kit/IL-33R complex and its functional relevance in vitro and in vivo.Therefore the specific aims of this project are:To perform structure/function analysis to identify the extracellular domains of the IL-33R which are critical to mediate complex formation with c-Kit. To investigate the influence of the c-Kit/IL-33R/Lyn complex formation in IL-33-induced and mast cell-dependent allergic reactions in vivo.

我们确定了在肥大细胞中激活的受体酪氨酸激酶c-Kit和IL-33 R之间的功能相关串扰。因此，c-Kit通过其配体干细胞因子（SCF）的活化诱导c-Kit与IL-33 R的相互作用，并增强肥大细胞中IL-33诱导的细胞因子产生。活化的c-Kit与未连接的IL-33 R的相互作用不仅是IL-33诱导其完全生物效应器功能的先决条件。此外，未连接的IL-33 R也是活化的c-Kit介导其完整信号传导（例如林恩和STAT活化素）所必需的。因此，未连接的IL-33 R为活化的c-Kit介导肥大细胞中SCF诱导的和Lyn-dependent的信号传导途径和效应子功能奠定了基础。然而，c-Kit/IL-33 R复合物形成背后的结构机制及其在体外和体内对SCF和/或IL-33诱导的肥大细胞效应器功能的影响尚不清楚。因此，本研究的总体目标是研究c-Kit/IL-33 R复合物形成的结构要求及其在体外和体内的功能相关性，因此，本项目的具体目标是：进行结构/功能分析，以确定IL-33 R的胞外结构域，这是介导与c-Kit形成复合物的关键。探讨c-Kit/IL-33 R/林恩复合物的形成对IL-33诱导的和肥大细胞依赖的过敏反应的影响。