Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Eur Heart J. 2012 Dec;33(24):3114-23. doi: 10.1093/eurheartj/ehr245. Epub 2011 Jul 30.
Interleukin-7 (IL-7) is a master regulator of T-cell development and homoeostasis. Increased IL-7 levels are associated with inflammatory diseases. The aims of this study were to determine whether IL-7 is a biomarker for inflammatory conditions or an active participant in atherogenesis.
Advanced atherosclerotic lesions in Apoe(-/-) mice were regressed by long-term cholesterol lowering through treatment with a helper-dependent adenovirus expressing apolipoprotein E (n= 6-10). Using this model, gene expression patterns in the aorta were analysed at an early phase of regression by microarray. After stringent statistical analysis, we found that IL-7 expression is significantly reduced in response to lowering of cholesterol (n= 6). To understand the importance of IL-7 down-regulation for atherosclerotic regression, we studied the effects and mechanisms of action of IL-7 on endothelial cells (ECs) in vitro as well as in vivo. Our major findings are: (i) IL-7 up-regulates cell adhesion molecules and monocyte chemoattractant protein-1 in ECs and promotes monocyte adhesion to ECs; (ii) this regulation is mediated by phosphatidylinositol 3-kinase (PI3K)/AKT-dependent and -independent activation of NF-κB; (iii) elevation of plasma IL-7 induces recruitment of monocytes/macrophages to endothelium without affecting plasma cholesterol (n= 5, 6); and (4) lack of IL-7 in bone marrow-derived cells reduces migration of monocytes/macrophages to the lesions (n= 5, 6).
These results suggest that IL-7 inflames endothelium via PI3K/AKT-dependent and -independent activation of NF-κB and recruits monocytes/macrophages to the endothelium, thus playing an active role in atherogenesis.
白细胞介素-7（IL-7）是 T 细胞发育和稳态的主要调节剂。IL-7 水平升高与炎症性疾病有关。本研究旨在确定 IL-7 是否是炎症状态的生物标志物，还是动脉粥样硬化形成的活性参与者。
通过用表达载脂蛋白 E 的辅助依赖性腺病毒（n=6-10）治疗来长期降低胆固醇，可使 Apoe（-/-）小鼠的晚期动脉粥样硬化病变消退。使用该模型，通过微阵列分析在消退的早期阶段分析主动脉中的基因表达模式。经过严格的统计分析，我们发现胆固醇降低后 IL-7 的表达显著降低（n=6）。为了了解 IL-7 下调对动脉粥样硬化消退的重要性，我们研究了 IL-7 对体外和体内内皮细胞（EC）的作用和作用机制。我们的主要发现是：（i）IL-7 在 EC 中上调细胞黏附分子和单核细胞趋化蛋白-1，并促进单核细胞黏附到 EC；（ii）这种调节是通过磷脂酰肌醇 3-激酶（PI3K）/AKT 依赖性和非依赖性 NF-κB 的激活介导的；（iii）血浆 IL-7 水平升高会诱导单核细胞/巨噬细胞募集到内皮而不影响血浆胆固醇（n=5,6）；（iv）骨髓源性细胞中缺乏 IL-7 会减少单核细胞/巨噬细胞向病变部位的迁移（n=5,6）。
这些结果表明，IL-7 通过 PI3K/AKT 依赖性和非依赖性 NF-κB 的激活使内皮发炎，并将单核细胞/巨噬细胞募集到内皮，从而在动脉粥样硬化形成中发挥积极作用。
