Liu Jing, Lin Jibin, He Shaolin, Wu Chun, Wang Boyuan, Liu Jie, Duan Yanping, Liu Tianxiao, Shan Shengshuai, Yang Keping, Dong Nianguo, Ji Qingwei, Huang Kai, Li Dazhu
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiology, Jingzhou hospital, Tongji Medical College, Huazhong University of Science and Technology, Jingzhou, China.
Cell Physiol Biochem. 2018;45(3):1034-1050. doi: 10.1159/000487344. Epub 2018 Feb 7.
BACKGROUND/AIMS: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved.
IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting.
Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4+ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis.
IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.
背景/目的：最近，研究表明白细胞介素-37（IL-37）参与动脉粥样硬化相关疾病。然而，IL-37在动脉粥样硬化中的调节机制仍不清楚。本研究旨在确定IL-37在动脉粥样硬化中的作用，并探讨其潜在机制。
采用免疫组织化学染色和实时逆转录聚合酶链反应（RT-PCR）检测人动脉粥样硬化斑块中IL-37的表达。用 Oil Red O 染色法测量斑块大小。分别通过流式细胞术分析和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）染色检测体内外细胞凋亡。通过蛋白质免疫印迹法检测IL-37、IL-18Rα和p-Smad3的蛋白表达水平。
免疫组织化学染色显示IL-37在人动脉粥样硬化斑块中高表达。细胞内细胞因子染色显示，浸润的CD4+T淋巴细胞和血管平滑肌细胞（VSMC）而非巨噬细胞是IL-37的主要来源。过表达IL-37的小鼠动脉粥样硬化负担显著改善，表现为斑块大小减小、胶原水平增加以及体内凋亡细胞数量减少。随后的机制研究表明，IL-37发挥抗动脉粥样硬化作用，至少部分是通过促进辅助性T细胞抗炎表型的分化来减轻炎症，并通过减少基质金属蛋白酶（MMP）-2/13介导的胶原降解和抑制VSMC凋亡来增加斑块稳定性。
IL-37可能是动脉粥样硬化性心脏病患者的一个新的潜在治疗靶点。
