Roles of Interleukin-17 in Endothelial Cells

IL-17 在内皮细胞中的作用

• 批准号: 8469079
• 负责人: Xiaofeng Yang
• 金额: $ 36.41万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469079
• 关键词: Adhesions; Adhesives; Antibodies; Apolipoprotein E; Arterial Fatty Streak; Attenuated; Autoimmune Diseases; Blood; Blood Vessels; Blood flow; CXCL1 gene; CXCL2 gene; Cell Adhesion; Cell Adhesion Molecules; Cells; Complex; Data; Development; Diet; Endothelial Cells; Fatty acid glycerol esters; Future; Gene Targeting; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Hyperlipidemia; Immune; Inflammation; Interleukin-17; Interleukin-6; Knock-out; Lead; Messenger RNA; Molecular; Mus; Names; Orphan; Plasma; Play; Production; Proteins; Publications; Receptor Signaling; Recruitment Activity; Regulation; Retinoids; Risk Factors; Role; Signal Pathway; Signal Transduction; Signaling Molecule; T-Cell Receptor; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; atherogenesis; autocrine; cell motility; chemokine; cytokine; feeding; interest; mRNA Expression; monocyte; novel therapeutics; protein expression; receptor; research study; response; success; transcription factor; vascular inflammation

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.

描述（由申请人提供）：白介素17在内皮细胞内皮细胞（EC）激活和炎症中的作用显着导致血管炎症。除了受到促炎/促性危险因素（例如高脂血症）的刺激外，ECS也是促炎细胞因子的靶标。自2003年以来，CD4+ RORT+（类维生素性相关的孤儿受体）T细胞的新谱系已通过其产生促炎细胞因子白介素17（IL-17）的产生来定义，因此被称为T-Helper 17（Th17）细胞。发现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。但是，一个重要的问题是，IL-17的分子信号通路是否在EC激活中起关键作用仍有待回答。因此，该提案的目的是检查一个中心假设，即高脂血症诱导的IL-17在EC激活中起着至关重要的作用。我们实验室和其他人的出版物以及我们的初步数据支持了这一假设：（i）IL-17受体A（IL-17RA）在主动脉ECS中表达。在EC中观察到高水平的IL-17受体C（IL-17RC）表达，表明功能受体复合物IL-17RA/C在EC中表达，并且能够响应IL-17刺激来启动信号传导。 （ii）IL-17在暴露于血流障碍的人主动脉EC中被上调，这是EC激活状况，这表明IL-17可以通过自分泌机制进一步刺激EC； （iii）血浆IL-17水平和Th17细胞在载脂蛋白E缺乏（APOE-/ - ）动脉粥样硬化小鼠中升高，这表明高脂血症使更多的IL-17可用于刺激ECS； （iv）抑制IL-17会抑制炎症。用抗体抑制IL-17会减轻APOE - / - 小鼠的血管炎症，这表明IL-17在血管炎症中起着至关重要的作用。我们对研究内皮激活和血管炎症的免疫调节有很长的兴趣。因此，我们拥有完成该项目的专业知识。将通过执行以下特定目的来实现此目标：（1）确定APOE - / - 小鼠主动脉EC中的IL-17信号通路是否上调； （2）确定IL-17诱导的人类EC激活是否在机械上取决于其促炎性细胞因子和趋化因子的上调； （3）确定IL-17基因耗竭是否抑制IL-17 - / - /APOE-/ - 小鼠中的EC激活。该项目非常重要，因为该项目的成功可能会导致未来开发用于治疗EC激活/炎症的新疗法。