Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis
Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis
复制标题
DOI：
10.4049/jimmunol.1100580
复制
发表时间：
2011-09-15
影响因子：
4.4
通讯作者：
Markovic-Plese, Silva
中科院分区：
文献类型：
--
作者：
Zhang, Xin;Tao, Yazhong;Markovic-Plese, Silva
继辛伐他汀在复发缓解型多发性硬化症（RR MS）患者中的临床试验证明了辛伐他汀抑制新的炎性CNS病变形成的能力之后，目前的体外研究表征了辛伐他汀抑制Th 17细胞分化的机制。他汀类药物的抗炎作用是通过抑制异戊二烯化来介导的，这确保了蛋白质的适当膜插入和功能。小GTP酶参与多种信号转导途径，是异戊二烯化的关键靶点。辛伐他汀是一种最疏水的他汀类药物，具有良好的CNS渗透性，可抑制RR MS患者体外分化的初始CD 4（+）T细胞中的Th 17细胞分化和IL-17 A、IL-17 F、IL-21和IL-22分泌。辛伐他汀对健康对照细胞的作用不太显著，因为它仅抑制IL-17 F分泌。通过抑制IFN调节因子4（IRF 4）的表达来介导对Th 17细胞分化的抑制，使用IRF 4基因敲低和过表达实验两者来鉴定IRF 4是人Th 17细胞分化的关键转录因子。在研究辛伐他汀抑制异戊二烯化途径-香叶基香叶基化或法尼基化时，我们证明香叶基香叶基转移酶抑制剂复制了辛伐他汀的作用。选择性抑制香叶基香叶基化RhoA相关激酶复制了辛伐他汀对IRF 4表达和IL-17 A、IL-17 F、IL-21和IL-22分泌的抑制作用，为这种致残性疾病提供了一种有希望的新治疗方法。免疫学杂志，2011，187：3431-3437。
Subsequent to the clinical trial of simvastatin in patients with relapsing remitting multiple sclerosis (RR MS), which demonstrated the ability of simvastatin to inhibit new inflammatory CNS lesion formation, the current in vitro study has characterized the mechanisms through which simvastatin inhibits Th17 cell differentiation. The anti-inflammatory effects of statins are mediated by the inhibition of isoprenylation, which ensures proper membrane insertion and function of proteins. Small GTPases, involved in multiple signal transduction pathways, are the key targets for isoprenylation. We report that simvastatin, one of the most hydrophobic statins with good CNS penetration, inhibited Th17 cell differentiation and IL-17A, IL-17F, IL-21, and IL-22 secretion in in vitro-differentiated naive CD4(+) T cells from RR MS patients. Simvastatin exerted a less prominent effect on the cells from healthy controls, as it inhibited only IL-17F secretion. The inhibition of Th17 cell differentiation was mediated via inhibition of IFN regulatory factor 4 (IRF4) expression, which was identified as a key transcription factor for human Th17 cell differentiation using both IRF4 gene knockdown and overexpression experiments. In studies addressing which isoprenylation pathway-geranylger-anylation or farnesylation-is inhibited by simvastatin, we demonstrated that the geranylgeranyl transferase inhibitor replicated the effect of simvastatin. Selective inhibition of geranylgeranylated RhoA-associated kinase replicated the effect of simvastatin on the inhibition of IRF4 expression and IL-17A, IL-17F, IL-21, and IL-22 secretion, presenting a promising new therapeutic approach for this disabling disease. The Journal of Immunology, 2011, 187: 3431-3437.