Youssef Sawsan, Stüve Olaf, Patarroyo Juan C, Ruiz Pedro J, Radosevich Jennifer L, Hur Eun Mi, Bravo Manuel, Mitchell Dennis J, Sobel Raymond A, Steinman Lawrence, Zamvil Scott S
Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine, Stanford University, Stanford, California 94305, USA.
Nature. 2002 Nov 7;420(6911):78-84. doi: 10.1038/nature01158.
Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are approved for cholesterol reduction, may also be beneficial in the treatment of inflammatory diseases. Atorvastatin (Lipitor) was tested in chronic and relapsing experimental autoimmune encephalomyelitis, a CD4(+) Th1-mediated central nervous system (CNS) demyelinating disease model of multiple sclerosis. Here we show that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming growth factor (TGF)-beta. Conversely, STAT4 phosphorylation was inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha) was suppressed. Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from EAE induction. Atorvastatin reduced CNS infiltration and major histocompatibility complex (MHC) class II expression. Treatment of microglia inhibited IFN-gamma-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-gamma-inducible expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's effects on antigen-presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T cells suppressed antigen-specific T-cell activation. Thus, atorvastatin has pleiotropic immunomodulatory effects involving both APC and T-cell compartments. Statins may be beneficial for multiple sclerosis and other Th1-mediated autoimmune diseases.
他汀类药物，即3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，已被批准用于降低胆固醇，在治疗炎症性疾病方面可能也有益处。阿托伐他汀（立普妥）在慢性复发性实验性自身免疫性脑脊髓炎中进行了测试，这是一种多发性硬化症的CD4(+) Th1介导的中枢神经系统（CNS）脱髓鞘疾病模型。在此我们表明，口服阿托伐他汀可预防或逆转慢性复发性麻痹。阿托伐他汀诱导STAT6磷酸化以及Th2细胞因子（白细胞介素（IL）-4、IL-5和IL-10）和转化生长因子（TGF）-β的分泌。相反，STAT4磷酸化受到抑制，Th1细胞因子（IL-2、IL-12、干扰素（IFN）-γ和肿瘤坏死因子（TNF）-α）的分泌受到抑制。阿托伐他汀促进Th0细胞向Th2细胞分化。在过继转移中，这些Th2细胞保护受体小鼠免受实验性自身免疫性脑脊髓炎的诱导。阿托伐他汀减少了中枢神经系统浸润以及主要组织相容性复合体（MHC）II类分子的表达。对小胶质细胞的处理抑制了多个MHC II类反式激活因子（CIITA）启动子处IFN-γ诱导的转录，并抑制了II类分子的上调。阿托伐他汀抑制了IFN-γ诱导的CD40、CD80和CD86共刺激分子的表达。HMG-CoA还原酶的产物l-甲羟戊酸逆转了阿托伐他汀对抗抗原呈递细胞（APC）和T细胞的作用。阿托伐他汀对APC或T细胞的处理均抑制了抗原特异性T细胞的激活。因此，阿托伐他汀具有涉及APC和T细胞区室的多效性免疫调节作用。他汀类药物可能对多发性硬化症和其他Th1介导的自身免疫性疾病有益。
