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Abstract：
The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations.
摘要：
JAK/STAT抑制剂的影响，用于各种炎症性疾病，心血管风险是有争议的，最近引起了安全问题。我们的研究调查了托法替尼对巨噬细胞胆固醇代谢的直接影响，这对动脉粥样硬化斑块的发展和稳定性至关重要。培养的人巨噬细胞THP-1用于通过放射性同位素方法评估托法替尼对细胞胆固醇流出和合成的影响，以及通过荧光测定法测量细胞胆固醇含量对胆固醇的摄取。胆固醇受体和供体是青少年特发性关节炎（JIA）患者和对照受试者的标准脂蛋白或血清。Tofacitinib显着增加了巨噬细胞胆固醇向所有受体的流出；它减少了正常和高胆固醇血症血清中的胆固醇摄取；并减少了胆固醇的合成。当使用未经治疗的JIA活动性疾病患者的血清作为胆固醇受体和供体时，tofacitinib治疗巨噬细胞能够增加胆固醇流出并降低胆固醇摄取，分别。总之,我们的体外数据支持托法替尼对巨噬细胞胆固醇代谢具有有利影响的概念，即使有风湿病患者的血清，并提示在部分患者人群中使用托法替尼可能与心血管风险相关的其他机制有关.
