Suppression of vascular endothelial cell inflammation

抑制血管内皮细胞炎症 适应性免疫和先天免疫都严格调控动脉粥样硬化。血管内皮细胞(ECs)是目标 促炎症细胞因子，如白介素1b(IL-1b)和肿瘤坏死因子-a(TNF-a)。然而， 血管内皮细胞是否在引发血管炎症中发挥关键作用这一重要问题仍然没有明确的定义。 特别是，动脉粥样硬化条件下的内皮细胞是否通过新定义的 炎症体仍不清楚。因此，这一提议的目标是检验一个新的假设，即 EC炎症伴随IL-1b的产生继而EC细胞凋亡加速在发病机制中的作用 动脉硬化。推论认为，抑制EC产生过量IL-2的因素和细胞 1B和EC细胞凋亡在动脉粥样硬化形成中起抑制作用。来自我们实验室的初步数据和来自 其他人的实验室明确支持这一假设：(I)微生物感染在肺炎的发病机制中发挥作用 动脉硬化。细菌脂多糖刺激小鼠主动脉内皮细胞 致动脉粥样硬化载脂蛋白E缺陷小鼠(MAECs)表达较高水平的前IL-1b 野生型对照小鼠的MAEC。ApoE-/-小鼠MAECs中PRO-IL-1b的上调 磷脂酰肌醇3-激酶(PI-3K)抑制剂Wortmannin和Ly294002的存在表明 PI3K-Akt生存通路抑制产生IL-1b的EC炎症；(Ii)我们发现了一种新的Bcl-XL 相互作用，抗凋亡蛋白TCTP。TCTP是PI3K途径的重要调节蛋白和抗凋亡蛋白。 AKT生存途径。此外，在内皮细胞中，TCTP也因内毒素刺激而下调， 提示抗TCTP可能通过PI-3K-Akt信号通路抑制内皮细胞炎症和细胞凋亡 内皮细胞的保护机制。此外，我们还发现ApoE-/-小鼠MAEC与 CD4+CD25HighFoxp+调节性T细胞(Tregs)导致前IL-1b表达降低，以应对内毒素， 提示免疫抑制树突起抑制EC炎症；(Iii)IL-1b缺乏抑制EC 炎症和动脉粥样硬化。因此，IL-1b产生抑制机制的阐明 EC炎症和EC细胞凋亡具有重要的临床意义，可能导致新的治疗方法。 动脉粥样硬化和血管炎症。将通过执行以下各项来实现这一目标 具体目标：(1)确定产生IL-1b的EC炎症在动脉粥样硬化中是否加速 APOE-/-小鼠与野生型对照小鼠的比较；(2)测定TCTP和PI3K-Akt 细胞内信号通路抑制ApoE-/-小鼠产生IL-1b的EC炎症和EC凋亡； 以及(3)确定细胞外抑制产生IL-1b的EC炎症和EC凋亡 Tregs可减轻ApoE-/-小鼠的动脉粥样硬化形成。

Suppression of vascular endothelial cell inflammation Both adaptive and innate immunity tightly regulate atherosclerosis. Vascular endothelial cells (ECs) are targets of proinflammatory cytokines, such as interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a). However, the important question of whether ECs play a critical role in initiating vascular inflammation remains poorly defined. In particular, the issue of whether ECs in atherogenic conditions generate excess IL-1b via the newly-defined inflammasome remains unknown. Therefore, the goal of this proposal is to examine a novel hypothesis that EC inflammation with the generation of IL-1b followed by EC apoptosis is accelerated in the pathogenesis of atherosclerosis. The corollary hypothesis is that factors and cells in suppressing EC generation of excess IL- 1b and EC apoptosis play inhibitory roles in atherogenesis. Preliminary data from our lab and reports from others' labs clearly support this hypothesis: (i) Microbial infections play a role in the pathogenesis of atherosclerosis. In response to the stimulation of bacterial lipopolysaccharide (LPS), mouse aortic ECs (MAECs) from atherogenic apolipoprotein E-deficient ApoE-/- mice express higher levels of pro-IL-1b than MAECs from wild-type control mice. The upregulation of pro-IL-1b in MAECs from ApoE-/- mice is increased in the presence of phosphatidylinositol 3-kinase (PI-3K) inhibitors Wortmannin and Ly294002, suggesting that PI3K-Akt survival pathway suppresses IL-1b-generating EC inflammation; (ii) We have identified a novel Bcl-xL interacting, anti-apoptotic protein TCTP. TCTP is an important regulator and anti-apoptotic protein along PI3K- Akt survival pathway. In addition, TCTP is also down-regulated in response to LPS stimulation in ECs, suggesting that anti-TCTP may inhibit EC inflammation and apoptosis as a PI-3K-Akt pathway-signaled protective mechanism of ECs. In addition, we found that co-culture of MAECs from ApoE-/- mice with CD4+CD25highFoxp+ regulatory T cells (Tregs) results in decreased pro-IL-1b expression in response to LPS, suggesting that immunosuppressive Tregs suppress EC inflammation; (iii) IL-1b deficiency inhibits EC inflammation and atherogenesis. Therefore, the elucidation of the suppressive mechanisms of IL-1b-generating EC inflammation and EC apoptosis is clinically significant, as it may lead to new therapeutics for treating atherosclerosis and vascular inflammation. This goal will be pursued through the execution of the following specific aims: (1) To determine whether IL-1b-generating EC inflammation is accelerated in atherogenic ApoE-/- mice in comparison to that in wild-type control mice; (2) To determine whether TCTP and PI3K-Akt intracellular signaling pathway inhibits IL-1b-generating EC inflammation and EC apoptosis in ApoE-/- mice; and (3) To determine whether extracellular suppression of IL-1b-generating EC inflammation and EC apoptosis by Tregs attenuates the atherogenesis in ApoE-/- mice.