Roles of Interleukin-17 in Endothelial Cells

描述（由申请人提供）：白细胞介素-17在内皮细胞中的作用内皮细胞（EC）活化和炎症显著促进血管炎症。除了被促炎/促动脉粥样硬化风险因素如高脂血症刺激外，EC也是促炎细胞因子的靶点。自2003年以来，CD 4 +RORt+（类维生素A相关孤儿受体）T细胞的新谱系已通过其产生促炎细胞因子白细胞介素-17（IL-17）而被定义，因此被命名为T辅助17（Th 17）细胞。这些细胞被发现在促进自身免疫性疾病和炎症中发挥重要作用。然而，IL-17的分子信号通路是否在EC活化中起关键作用的重要问题仍有待回答。因此，本提案的目标是检验一个中心假设，即高脂血症诱导的IL-17在EC激活中起关键作用。本实验室和其他实验室的文献以及我们的初步数据支持这一假设：（i）IL-17受体A（IL-17 RA）在主动脉EC中表达。在EC中观察到高水平的IL-17受体C（IL-17 RC）表达，表明功能性受体复合物IL-17 RA/C在EC中表达并且能够响应于IL-17刺激而启动信号传导;（ii）IL-17在暴露于干扰血流（EC活化条件）的人主动脉EC中上调，表明EC可通过自分泌机制被IL-17进一步刺激;（iii）载脂蛋白E缺乏的内皮细胞中血浆IL-17水平和Th 17细胞升高，（iv）抑制IL-17可抑制炎症。用抗体抑制IL-17减弱ApoE-/-小鼠中的血管炎症，表明IL-17在血管炎症中起关键作用。我们对内皮激活和血管炎症的免疫调节研究有着长期的兴趣。因此，我们有能力完成这个项目。（1）确定IL-17信号通路是否在ApoE-/-小鼠的主动脉EC中上调;（2）确定IL-17诱导的人EC活化是否在机制上依赖于其促炎细胞因子和趋化因子的上调;（3）检测IL-17基因缺失是否抑制IL-17-/-/ApoE-/-小鼠EC活化。该项目具有重要意义，因为该项目的成功可能导致未来开发用于治疗EC活化/炎症的新疗法。

DESCRIPTION (provided by applicant): Roles of Interleukin-17 in Endothelial Cells Endothelial cell (EC) activation and inflammation significantly contribute to vascular inflammation. In addition to being stimulated by proinflammatory/proatherogenic risk factors such as hyperlipidemia, ECs are also the target of proinflammatory cytokines. Since 2003, a new lineage of CD4+RORt+ (retinoid-related orphan receptor) T cells has been defined by its production of proinflammatory cytokine interleukin-17 (IL-17) and hence named T-helper 17 (Th17) cells. These cells are found to play an essential role in promoting autoimmune diseases and inflammation. However, an important question of whether molecular signaling pathway of IL-17 plays a critical role in EC activation remains to be answered. Therefore, the goal of this proposal is to examine a central hypothesis that IL-17, induced by hyperlipidemia, plays a critical role in EC activation. The publications from our labs and others' as well as our preliminary data support this hypothesis: (i) IL-17 receptor A (IL-17RA) is expressed in aortic ECs. High levels of IL-17 receptor C (IL-17RC) expression are observed in ECs, suggesting the functional receptor complex IL-17RA/C is expressed in ECs and is able to initiate signaling in response to IL-17 stimulation; (ii) IL-17 is upregulated in human aortic ECs exposed to disturbed blood flow, an EC activation condition, suggesting that ECs can be further stimulated by IL-17 via an autocrine mechanism; (iii) Plasma IL-17 level and Th17 cells are elevated in apolipoprotein E deficient (ApoE-/- ) atherogenic mice, suggesting that hyperlipidemia makes more IL-17 available to stimulate ECs; and (iv) Inhibition of IL-17 suppresses inflammation. Inhibition of IL-17 with antibodies attenuates vascular inflammation in ApoE-/- mice, suggesting that IL-17 plays a critical role in vascular inflammation. We have a long standing interest in studying immune regulation of endothelial activation and vascular inflammation. Therefore, we have the expertise to complete this project. This goal will be pursued through the execution of the following specific aims: (1) To determine whether IL-17 signaling pathway is upregulated in aortic ECs in ApoE-/- mice; (2) To determine whether IL-17-induced human EC activation is mechanistically dependent on its upregulation of proinflammatory cytokines and chemokines; (3) To determine whether IL-17 gene depletion inhibits EC activation in IL-17-/-/ApoE-/- mice. This project is significant since success of this project may lead to future development of new therapeutics for treating EC activation/inflammation.