The statin family of therapeutics is widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is a key mechanism of action. In this study, we performed full transcriptomic RNA sequencing and qPCR to evaluate the effects of mevalonate on the immunoregulatory phenotype of endothelial cells (EC). We find that mevalonate-dependent gene regulation includes a reduction in the expression of multiple pro-inflammatory genes including TNFSF4 (OX40-L) and TNFSF18 (GITR-L) and a co-incident induction of immunoregulatory genes including LGALS3 (Galectin-3) and LGALS9 (Galectin-9). In functional assays, pretreatment of EC with simvastatin to inhibit mevalonate metabolism resulted in a dose-dependent reduction in the costimulation of CD45RO⁺CD4⁺ T cell proliferation as well as IL-2, IFNγ and IL-6 production versus vehicle-treated EC. In contrast, pre-treatment of EC with L-mevalonate in combination with simvastatin reversed phenotypic and functional responses. Collectively, these results indicate that relative mevalonate metabolism by EC is critical to sustain EC-dependent mechanisms of immunity. Our findings have broad relevance for the repurposing of statins as therapeutics to augment immunoregulation and/or to inhibit local tissue pro-inflammatory cytokine production following transplantation.

中文翻译：

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他汀类药物抑制甲羟戊酸代谢可增强血管内皮细胞的免疫调节表型并抑制 CD4+ T 细胞的共刺激

他汀类药物在临床上被广泛用作降胆固醇药物，它们靶向细胞内甲羟戊酸生成的作用是一个关键的作用机制。在这项研究中，我们进行了完整的转录组 RNA 测序和 qPCR，以评估甲羟戊酸对内皮细胞 (EC) 免疫调节表型的影响。我们发现甲羟戊酸依赖性基因调控包括减少多种促炎基因的表达，包括 TNFSF4 (OX40-L) 和 TNFSF18 (GITR-L)，以及同时诱导免疫调节基因，包括 LGALS3 (Galectin-3)和 LGALS9（半乳糖凝集素 9）。^{在功能测定中，用辛伐他汀预处理 EC 以抑制甲羟戊酸代谢导致 CD45RO +} CD4 ⁺的共刺激剂量依赖性降低与载体处理的 EC 相比，T 细胞增殖以及 IL-2、IFNγ 和 IL-6 的产生。相反，用 L-甲羟戊酸联合辛伐他汀对 EC 进行预处理可逆转表型和功能反应。总的来说，这些结果表明 EC 的相对甲羟戊酸代谢对于维持 EC 依赖性免疫机制至关重要。我们的研究结果与将他汀类药物重新用作治疗剂以增强免疫调节和/或抑制移植后局部组织促炎细胞因子产生具有广泛的相关性。