Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis.
Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis.
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DOI：
10.1096/fj.02-1014fje
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发表时间：
2003-05
期刊：
影响因子：
--
通讯作者：
Adamson P
中科院分区：
文献类型：
--
作者：
Greenwood J;Walters CE;Pryce G;Kanuga N;Beraud E;Baker D;Adamson P
神经炎症性疾病，如多发性硬化症(MS)，是由异常的白细胞进入中枢神经系统(CNS)引起的。为了突破特殊的血脑屏障，激活的白细胞与中枢神经系统内皮细胞(EC)相互作用，激活CD54介导的控制Rho GTP酶的信号通路。为了正确发挥作用，Rho需要翻译后的异戊二烯基化，这可以通过用HMG-CoA还原酶抑制剂(他汀类药物)抑制胆固醇合成途径来耗尽异戊二烯的供应来抑制。在这里，我们表明，洛伐他汀处理体外脑内皮细胞可抑制Rho介导的跨内皮T细胞迁移。这种作用可以通过补充HMG-CoA还原酶的下游产物甲伐内酯或异位表达肉豆蔻酰化的Rho来逆转，该Rho在没有预烯基化的情况下仍保持活性。在复发-缓解型多发性硬化症小鼠模型中，洛伐他汀治疗抑制了白细胞向中枢神经系统的迁移，显著减缓了急性和复发临床疾病的发展。这些研究表明，他汀类药物对脑内皮细胞中Rho蛋白的间接药理抑制可以抑制神经炎症发病机制中的一个关键阶段，即白细胞跨血脑屏障迁移。这些研究证明了他汀类药物在调节神经炎症性疾病的免疫反应中的新作用，并可能为其在治疗MS中的使用提供更多的理论依据。
Neuroinflammatory diseases, such as multiple sclerosis (MS), result from aberrant leucocyte traffic into the central nervous system (CNS). To breach the specialized blood-brain barrier, activated leucocytes interact with CNS endothelial cells (EC) and activate a CD54-mediated signaling pathway controlling the Rho GTPase. To function correctly Rho requires post-translational prenylation, and this can be inhibited by depleting the supply of isoprenoids through inhibition of the cholesterol synthesis pathway with HMG-CoA reductase inhibitors (statins). Here we show that treatment of brain EC in vitro with lovastatin inhibits Rho-mediated transendothelial T cell migration. This effect can be reversed by supplementation with mevalonolactone, the downstream product of HMG-CoA reductase, or by ectopic expression of myristoylated Rho, which remains active in the absence of prenylation. In a relapsing-remitting mouse model of MS, lovastatin treatment inhibited leucocyte migration into the CNS and significantly attenuated the development of both acute and relapsing clinical disease. These studies demonstrate that the indirect pharmacological inhibition of Rho proteins in brain EC by statins can inhibit a key stage in the pathogenesis of neuroinflammation, namely leucocyte migration across the blood-brain barrier. Theses studies demonstrate a novel effect of statins in modulating the immune response in neuroinflammtory diseases and may provide additional rationale for their use in the treatment of MS.
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影响因子：
4.3
作者：
ALLEN, SJ;BAKER, D;TURK, JL
通讯作者：
TURK, JL
影响因子：
9.9
作者：
Neuhaus, O;Strasser-Fuchs, S;Archelos, JJ
通讯作者：
Archelos, JJ
DOI：
10.4049/jimmunol.168.8.4087
发表时间：
2002-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Walters CE;Pryce G;Hankey DJR;Sebti SM;Hamilton AD;Baker D;Greenwood J;Adamson P
通讯作者：
Adamson P
影响因子：
3.3
作者：
ONEILL, JK;BAKER, D;TURK, JL
通讯作者：
TURK, JL
影响因子：
2.5
作者：
Stanislaus, R;Pahan, K;Singh, I
通讯作者：
Singh, I