Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei 11490, Taiwan.
Int J Mol Sci. 2019 Jul 19;20(14):3534. doi: 10.3390/ijms20143534.
Statins inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase are the standard treatment for hypercholesterolemia in atherosclerotic cardiovascular disease (ASCVD), mediated by inflammatory reactions within vessel walls. Several studies highlighted the pleiotropic effects of statins beyond their lipid-lowering properties. However, few studies investigated the effects of statins on T cell activation. This study evaluated the immunomodulatory capacities of three common statins, pitavastatin, atorvastatin, and rosuvastatin, in activated human T cells. The enzyme-linked immunosorbent assay (ELISA) and quantitative real time polymerase chain reaction (qRT-PCR) results demonstrated stronger inhibitory effects of pitavastatin on the cytokine production of T cells activated by phorbol 12-myristate 13-acetate (PMA) plus ionomycin, including interleukin (IL)-2, interferon (IFN)-γ, IL-6, and tumor necrosis factor α (TNF-α). Molecular investigations revealed that pitavastatin reduced both activating protein-1 (AP-1) DNA binding and transcriptional activities. Further exploration showed the selectively inhibitory effect of pitavastatin on the signaling pathways of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK). Our findings suggested that pitavastatin might provide additional benefits for treating hypercholesterolemia and ASCVD through its potent immunomodulatory effects on the suppression of ERK/p38/AP-1 signaling in human T cells.
他汀类药物抑制 3-羟基-3-甲基戊二酰辅酶 A 还原酶是动脉粥样硬化性心血管疾病（ASCVD）中高胆固醇血症的标准治疗方法，其作用机制是通过血管壁内的炎症反应。多项研究强调了他汀类药物除了降低血脂作用之外的多种作用。然而，很少有研究调查他汀类药物对 T 细胞激活的影响。本研究评估了三种常见的他汀类药物，即匹伐他汀、阿托伐他汀和罗苏伐他汀，在激活的人 T 细胞中的免疫调节能力。酶联免疫吸附测定（ELISA）和实时定量聚合酶链反应（qRT-PCR）结果表明，匹伐他汀对佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）加离子霉素激活的 T 细胞产生细胞因子（包括白细胞介素（IL）-2、干扰素（IFN）-γ、IL-6 和肿瘤坏死因子-α（TNF-α））的抑制作用更强。分子研究表明，匹伐他汀降低了激活蛋白-1（AP-1）的 DNA 结合和转录活性。进一步研究表明，匹伐他汀选择性抑制细胞外信号调节激酶（ERK）和 p38 丝裂原活化蛋白激酶（MAPK）信号通路，但不抑制 c-Jun N-末端激酶（JNK）。我们的研究结果表明，匹伐他汀可能通过对人 T 细胞中 ERK/p38/AP-1 信号通路的抑制作用发挥其强大的免疫调节作用，为治疗高胆固醇血症和 ASCVD 提供额外的益处。
