Role of a novel IL18 binding protein in atherosclerosis

新型 IL18 结合蛋白在动脉粥样硬化中的作用

基本信息

批准号：
8882740
负责人：
GUO-PING SHI
金额：
$ 42.04万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-21 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8882740
关键词：
Adhesions Affect Affinity Age Aldosterone Angiotensin II Aorta Apolipoprotein E Apoptosis Area Arterial Fatty Streak Atherosclerosis Binding Biological Models Blood Vessels Bone Marrow Cells CCL2 gene COS-7 Cell Cardiovascular system Cations Cell Proliferation Cell surface Cells Chest Chloride Ion Chlorides Congestive Heart Failure Cytokine Signaling Deposition Development Disease Distal convoluted renal tubule structure Endothelial Cells Event Future Genetic Health Heart Human Hypokalemic alkalosis Hypomagnesemia IL6 gene Inflammation Inflammatory Inherited Interferon Type II Interleukin-1 beta Interleukin-18 Ion Channel Ion Channel Protein Kidney Knowledge Lead Lesion Lipids Mediating Metolazone Molecular Mus Pathway interactions Patients Phenotype Phosphorylation Site Phosphotransferases Production Proteins Recombinant Interleukin-18 Role Secondary to Serum Severities Signal Pathway Signal Transduction Smooth Muscle Myocytes Sodium Chloride Sodium-Restricted Diet Syndrome T-Lymphocyte Testing Tumor Necrosis Factor-alpha Tyrosine Phosphorylation abdominal aorta age related aortic arch atherogenesis cardiovascular risk factor cell motility chemokine cytokine hypertensive heart disease interleukin-18 binding protein interleukin-18 receptor intraperitoneal macrophage novel overexpression receptor symporter uptake

项目摘要

DESCRIPTION (provided by applicant): Na-Cl co-transporter (NCC) is a 125-kDa 12-transmembrane Na+-dependent cation-chloride co-transporter that is primarily expressed in kidney distal convoluted tubules to resorb the filtered load of NaCl in the kidney. In mice, deficiency of NCC causes Gitelman syndrome, an inherited hypokalemic alkalosis with significant hypocalciuria and hypomagnesemia, which are secondary to the deficit in NaCl resorption. Interleukin 18 (IL18) is an inflammatory cytokine that promotes inflammatory cell cytokine/chemokine (e.g., IFN-γ, IL6, MCP-1) production. In atherosclerotic lesions, increased levels of IL18 and its cognate receptor IL18r are detected in macrophages, smooth muscle cells (SMCs), and endothelial cells (ECs). Serums IL18 levels are elevated in patients with CAD, correlate with CAD severity score, are associated with cardiovascular risk factors, and predict future CAD events. In experimental atherosclerosis, overexpression or intraperitoneal administration of IL18 increases atherosclerotic lesion formation and enhances vulnerable plaque phenotypes via an IFN-γ- dependent pathway, while inactivation or genetic deficiency of IL18 slows lesion progression. Our preliminary studies show that IL18 binds to NCC and mediates downstream protein tyrosine phosphorylation in mouse heart ECs. Stimulation of macrophages, T cells, and aortic SMCs and ECs with inflammatory cytokines (e.g., IL18, TNF-α, IL1ß) induces NCC expression. In both humans and mice, normal aortas express negligible NCC and IL18r, but SMCs, ECs, and macrophages in atherosclerotic lesions express high amounts of both NCC and IL18r. In atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice, the absence of either IL18r or NCC does not slow atherosclerosis development significantly. But combined deficiency of IL18r and NCC significantly reduces aortic arch macrophage content and lesion areas, and thoracic-abdominal aorta lipid deposition, along with reduced serum cytokines IFN-γ and IL6. From cultured macrophages, the combined absence of NCC and IL18r impairs IL18-mediated cell signaling, and significantly reduces IL18 cell-surface binding and consequent inflammatory cytokine and chemokine production. These observations lead to our central hypothesis that NCC and IL18r are alternative IL18-binding molecules on inflammatory cells and cardiovascular cells, and that they mediate IL18 activities cooperatively in atherogenesis and possibly in other inflammatory diseases. We propose three aims: 1). to examine whether inhibition, activation, or genetic deficiency of NCC affects atherogenesis; whether NCC activities on inflammatory cells (e.g. macrophages) are essential to atherogenesis; and age-dependent; 2). To examine whether NCC acts like other kinase receptor, NCC activities in salt uptake and IL18 signaling interplay with each other, IL18 has different affinity for NCC and IL18r, and NCC is specific for IL18; and 3). To examine whether NCC mediates IL18 activities in T cells and vascular SMCs and ECs.

描述（由申请人提供）：Na-Cl 协同转运蛋白 (NCC) 是一种 125 kDa 12 次跨膜 Na+ 依赖性阳离子-氯化物协同转运蛋白，主要在肾脏远曲小管中表达，以重新吸收肾脏中过滤的 NaCl 负荷。在小鼠中，NCC 缺乏会导致 Gitelman 综合征，这是一种遗传性低钾性碱中毒，伴有严重的低钙尿症和低镁血症是继发于 NaCl 吸收缺陷的白细胞介素 18 (IL18) 是一种炎症细胞因子，可促进炎症细胞细胞因子/趋化因子（例如 IFN-γ、IL6、MCP-1）的产生。 IL18 及其同源受体 IL18r 在巨噬细胞、平滑肌细胞 (SMC) 和内皮细胞 (EC) 中检测到。 CAD 患者的血清 IL18 水平升高，与 CAD 严重程度评分相关，与心血管危险因素相关，并可预测未来的 CAD 事件。在实验性动脉粥样硬化中，IL18 的过度表达或腹膜内给药会增加动脉粥样硬化病变的形成，并通过以下方式增强易损斑块表型。 IFN-γ 依赖性途径，而 IL18 失活或遗传缺陷会减缓病变进展。我们的初步研究表明，IL18 与 NCC 结合并介导下游蛋白。小鼠心脏 EC 中的酪氨酸磷酸化。用炎症细胞因子（例如 IL18、TNF-α、IL1ß）刺激巨噬细胞、T 细胞和主动脉 SMC 会诱导 NCC 表达。在人类和小鼠中，正常主动脉表达可忽略不计的 NCC 和 IL18r。，但动脉粥样硬化病变中的 SMC、EC 和巨噬细胞均表达大量 NCC在易发生动脉粥样硬化的载脂蛋白 E 缺陷 (Apoe-/-) 小鼠中，IL18r 或 NCC 的缺失不会显着减缓动脉粥样硬化的发展，但 IL18r 和 NCC 的联合缺乏会显着降低主动脉弓巨噬细胞含量和病变区域。和胸腹主动脉脂质沉积，以及来自培养的巨噬细胞的血清细胞因子 IFN-γ 和 IL6 的减少。 NCC 和 IL18r 的缺失会损害 IL18 介导的细胞信号传导，并显着减少 IL18 细胞表面结合以及随后的炎症细胞因子和趋化因子的产生。这些观察结果得出我们的中心假设，即 NCC 和 IL18r 是炎症细胞和心血管上的替代 IL18 结合分子。细胞，并且它们在动脉粥样硬化形成和可能的其他炎症性疾病中协同介导 IL18 活性：1）检查是否抑制、激活或遗传缺陷。 NCC 影响动脉粥样硬化形成；NCC 对炎症细胞（例如巨噬细胞）的活性是否对动脉粥样硬化形成至关重要；以及年龄依赖性；2) 检查 NCC 的作用是否与其他激酶受体一样，以及 NCC 在盐摄取和 IL18 信号传导方面的相互作用。 IL18对NCC和IL18r具有不同的亲和力，并且NCC对IL18具有特异性；3)检测NCC是否介导T细胞和血管中的IL18活性； SMC 和 EC。