Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin.
Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin.
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DOI：
10.1084/jem.20051129
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发表时间：
2006-02-20
期刊：
影响因子：
--
通讯作者：
Steinman L
中科院分区：
文献类型：
--
作者：
Dunn SE;Youssef S;Goldstein MJ;Prod'homme T;Weber MS;Zamvil SS;Steinman L
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶是甲羟戊酸途径中的关键酶，其调节胆固醇以及类异戊二烯的生物合成，类异戊二烯介导某些GTP酶的膜结合。阿托伐他汀（AT）阻断这种酶可抑制实验性自身免疫性脑脊髓炎期间破坏性促炎性T辅助细胞（Th）1反应，并可能有益于治疗多发性硬化症和其他Th 1介导的自身免疫性疾病。在这里，我们提出的证据连接特定的类异戊二烯中间体的甲羟戊酸途径的信号转导途径，调节T细胞自身免疫。我们证明，类异戊二烯香叶基香叶基焦磷酸（GGPP）介导的增殖，而GGPP和它的前体，法尼基-PP，调节髓鞘反应性T细胞的Th 1分化。这些类异戊二烯中间体在体内通过口服AT给药的消耗阻碍了这些T细胞的反应，通过减少香叶基香叶基RhoA和法尼基化Ras在质膜。这与细胞外信号调节激酶（ERK）和p38磷酸化减少以及响应T细胞受体活化的共同靶点c-fos的DNA结合有关。ERK和p38的抑制模仿AT的作用，并诱导Th 2细胞因子转移。因此，通过连接类异戊二烯的可用性调节Th 1/Th 2的命运，我们已经阐明了一种机制，AT可以抑制Th 1介导的中枢神经系统自身免疫性疾病。
3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal–regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease.
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影响因子：
20.3
作者：
Goldman, F;Hohl, RJ;Koretzky, G
通讯作者：
Koretzky, G
DOI：
10.1096/fj.02-1014fje
发表时间：
2003-05
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Greenwood J;Walters CE;Pryce G;Kanuga N;Beraud E;Baker D;Adamson P
通讯作者：
Adamson P
影响因子：
3.7
作者：
Naderi, S;Blomhoff, R;Blomhoff, HK
通讯作者：
Blomhoff, HK
影响因子：
4.8
作者：
Holstein, SA;Wohlford-Lenane, CL;Hohl, RJ
通讯作者：
Hohl, RJ
洛伐他汀抑制自身免疫性视网膜疾病不需要 Th2 细胞因子诱导。
DOI：
10.4049/jimmunol.174.4.2327
发表时间：
2005-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Harry R;Gegg M;Hankey D;Zambarakji H;Pryce G;Baker D;Calder V;Adamson P;Greenwood J
通讯作者：
Greenwood J