Universitätsklinik und Poliklinik für Innere Medizin III, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.
J Cell Mol Med. 2011 Apr;15(4):994-1004. doi: 10.1111/j.1582-4934.2010.01036.x.
Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti-inflammatory capacities, in addition to their lipid-lowering effects. We investigated the anti-inflammatory effect of statins in the cytokine-mediated-interaction-model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis-related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic (i.e. over-additive) IL-6 (interleukin-6) production as measured in ELISA. Recombinant IL-1, tumour necrosis factor-α and IL-6 mediated the synergistic IL-6 production. The standard anti-inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL-6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL-6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL-6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL-6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL-6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti-inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine-mediated innate inflammatory pathways in the vessel wall.
炎症途径参与动脉粥样硬化的发生。细胞因子介导的血管壁细胞与浸润的单核细胞相互作用可能引发局部炎症过程。3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂（他汀类药物）是心血管疾病的标准药物。除了降低血脂的作用外，它们还具有抗炎作用。我们研究了他汀类药物在人血管平滑肌细胞（SMC）和人单核细胞（MNC）的细胞因子介导的相互作用模型中的抗炎作用。在这个与动脉粥样硬化相关的炎症模型中，LPS（脂多糖，内毒素）以及高迁移率族蛋白 1 刺激导致 IL-6（白细胞介素-6）的协同（即超加性）产生，如 ELISA 所测量的。重组 IL-1、肿瘤坏死因子-α 和 IL-6 介导协同的 IL-6 产生。标准抗炎药物阿司匹林和吲哚美辛（Indo）将协同的 IL-6 产生减少了 60%。辛伐他汀、阿托伐他汀、氟伐他汀或普伐他汀将 IL-6 的产生分别减少了 53%、50%、64%和 60%。抑制作用呈剂量依赖性。他汀类药物与阿司匹林和/或 Indo 联合使用可完全抑制协同的 IL-6 产生。相同的抑制剂阻断了 STAT3 的磷酸化，为 IL-6 在协同作用中的自分泌作用提供了证据。志愿者在 5 天接受阿司匹林或辛伐他汀治疗后，MNC 显示出的 IL-6 产生无明显减少，这可能是由于在 MNC 分离过程中药物被清除。总之，这些数据表明，在这种新型的 SMC/MNC 共培养模型中，可以敏感和可重复地确定抗炎功能（此处显示为他汀类药物）。这些数据表明，他汀类药物通过调节血管壁中细胞因子介导的固有炎症途径，具有影响动脉粥样硬化的能力。
