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）的激活和炎症显著地促进血管炎症。除了受到高脂血症等促炎/促动脉粥样硬化危险因素的刺激外，内皮细胞也是促炎细胞因子的靶点。自2003年以来，一种新的CD4+RORt+（类维生素a相关孤儿受体）T细胞谱系被定义为产生促炎细胞因子白介素-17 (IL-17)，因此被命名为T辅助17 （Th17）细胞。这些细胞在促进自身免疫性疾病和炎症中起着至关重要的作用。然而，IL-17的分子信号通路是否在EC激活中起关键作用仍然是一个重要的问题。因此，本研究的目的是检验一个中心假设，即由高脂血症诱导的IL-17在EC激活中起关键作用。我们实验室和其他实验室的出版物以及我们的初步数据支持这一假设：(i) IL-17受体A （IL-17RA）在主动脉内皮细胞中表达。在ECs中观察到IL-17受体C （IL-17RC）的高水平表达，表明功能性受体复合物IL-17RA/C在ECs中表达，并能够启动响应IL-17刺激的信号传导；（ii） IL-17在暴露于血流紊乱的人主动脉内皮细胞中表达上调，这表明IL-17可以通过自分泌机制进一步刺激内皮细胞；（iii）载脂蛋白E缺乏（ApoE-/-）致动脉粥样硬化小鼠血浆IL-17水平和Th17细胞升高，提示高脂血症使更多IL-17可用于刺激ECs；（iv）抑制IL-17可抑制炎症。抗体抑制IL-17可减轻ApoE-/-小鼠的血管炎症，提示IL-17在血管炎症中起关键作用。我们对研究内皮细胞活化和血管炎症的免疫调节有着长期的兴趣。因此，我们有能力完成这个项目。这一目标将通过执行以下具体目标来实现：(1)确定IL-17信号通路是否在ApoE-/-小鼠的主动脉内皮细胞中上调；(2)确定il -17诱导的人EC激活是否机制依赖于其对促炎细胞因子和趋化因子的上调；(3)确定IL-17基因缺失是否抑制IL-17-/-/ApoE-/-小鼠EC活化。这个项目意义重大，因为这个项目的成功可能会导致未来治疗EC激活/炎症的新疗法的发展。

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.