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密切调节动脉粥样硬化。血管内皮细胞（EC）是靶细胞， 促炎细胞因子，如白细胞介素-1b（IL-1b）和肿瘤坏死因子-a（TNF-α）。但 内皮细胞是否在引发血管炎症中起关键作用的重要问题仍然不清楚。 特别是，在致动脉粥样硬化的条件下，EC是否通过新定义的IL-1b产生过量的IL-1b， 炎性小体仍然未知。因此，本提案的目的是检验一个新的假设， EC炎症伴随IL-1b的产生，随后是EC凋亡，这在炎症的发病机制中是加速的。 动脉粥样硬化推论假设是，抑制EC产生过量IL-1的因子和细胞 1b和EC凋亡在动脉粥样硬化形成中起抑制作用。我们实验室的初步数据和 其他人的实验室清楚地支持这一假设：（i）微生物感染在 动脉粥样硬化在细菌脂多糖（LPS）刺激下，小鼠主动脉内皮细胞 来自致动脉粥样硬化的载脂蛋白E缺陷型ApoE-/-小鼠的MAEC（MAECs）表达的pro-IL-1b水平高于 来自野生型对照小鼠的MAEC。ApoE-/-小鼠MAECs中pro-IL-1b的上调增加， 磷脂酰肌醇3-激酶（PI-3 K）抑制剂Wortmannin和Ly 294002的存在，表明 PI 3 K-Akt存活通路抑制产生IL-1b的EC炎症;（ii）我们已经鉴定了一种新的Bcl-xL 相互作用的抗凋亡蛋白TCTP。TCTP是沿着PI 3 K的重要调节因子和抗凋亡蛋白。 Akt生存通路。此外，TCTP也在EC中响应于LPS刺激而下调， 提示抗TCTP可能通过PI-3 K-Akt通路抑制EC炎症和凋亡， EC的保护机制。此外，我们发现来自ApoE-/-小鼠的MAECs与 CD 4 + CD 25 highFoxp+调节性T细胞（Tcells）导致响应于LPS的pro-IL-1b表达降低， 提示免疫抑制性Tcl 4抑制EC炎症;（iii）IL-1b缺乏抑制EC 炎症和动脉粥样硬化形成。因此，阐明IL-1b产生的抑制机制， EC炎症和EC凋亡具有临床意义，因为它可能导致治疗EC炎症和EC凋亡的新疗法。 动脉粥样硬化和血管炎症。为实现这一目标，将执行下列措施： 具体目的：（1）确定在动脉粥样硬化形成过程中，产生IL-1b的EC炎症是否加速 ApoE-/-小鼠与野生型对照小鼠的比较;（2）为了确定TCTP和PI 3 K-Akt是否在ApoE-/-小鼠中表达， 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凋亡是否 通过TdR减弱ApoE-/-小鼠中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.