Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Immunol. 2011 Sep 15;187(6):3431-7. doi: 10.4049/jimmunol.1100580. Epub 2011 Aug 19.
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--geranylgeranylation 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.
在复发缓解型多发性硬化症（RRMS）患者中进行辛伐他汀的临床试验后，证明了辛伐他汀能够抑制新的中枢神经系统炎症性病变的形成，目前的体外研究已经确定了辛伐他汀抑制 Th17 细胞分化的机制。他汀类药物的抗炎作用是通过抑制异戊烯化来介导的，这确保了蛋白质的适当膜插入和功能。小 GTPases 参与多种信号转导途径，是异戊烯化的关键靶标。我们报告称，辛伐他汀是最具亲脂性且具有良好中枢神经系统穿透力的他汀类药物之一，可抑制 RRMS 患者体外分化的幼稚 CD4+T 细胞中的 Th17 细胞分化和白细胞介素-17A（IL-17A）、白细胞介素-17F（IL-17F）、白细胞介素-21（IL-21）和白细胞介素-22（IL-22）的分泌。辛伐他汀对来自健康对照者的细胞的作用不那么明显，因为它仅抑制 IL-17F 的分泌。Th17 细胞分化的抑制是通过抑制干扰素调节因子 4（IRF4）的表达来介导的，通过使用 IRF4 基因敲低和过表达实验，IRF4 被确定为人类 Th17 细胞分化的关键转录因子。在研究辛伐他汀抑制的异戊烯化途径——香叶基香叶基转移酶或法呢基转移酶——时，我们证明了香叶基香叶基转移酶抑制剂复制了辛伐他汀的作用。选择性抑制法尼基化 RhoA 相关激酶复制了辛伐他汀对 IRF4 表达和白细胞介素-17A（IL-17A）、白细胞介素-17F（IL-17F）、白细胞介素-21（IL-21）和白细胞介素-22（IL-22）分泌的抑制作用，为这种使人丧失能力的疾病提供了一种有前途的新治疗方法。
