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Putative Immune Regulatory Role of Statins

机译:他汀类药物的假定免疫调节作用

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Statins, which are mainly used for treatment of hypercholesterolemia because of their lipid-lowering effects, may also display many immunomodulatory properties. Statins interfere in the mevalonate pathway through inhibition of HMG-CoA reductase activity and thereby affect isoprenylation of proteins and cholesterol biosynthesis. Besides lowering blood cholesterol levels, statins inhibit the production of pro-inflammatory cytokines and reduce membrane expression of several immunoregulatory molecules, including major histocompatibility complex class II (MHC-II) molecules. In this review we discuss the putative immunomodulatory role of statins and the mechanism by which simvastatin reduces the membrane expression of MHC-II molecules on several cell types, emphasizing on the disruption of cholesterol-containing microdomains, or lipid rafts, which transport and concentrate MHC-II molecules to the cell surface. Because glycosylphosphatidylinositol (GPI)-linked proteins are in general characteristic components of biochemically defined lipid rafts, and rely for transport and function at the cell surface on the integrity of these cholesterol-containing vesicles, we argue that statins, by disrupting these vesicles, also affect the expression of other immunoregulatory molecules. In addition, we also argue that statins inhibit the activation and intracellular transport of various proteins by interfering in protein isoprenylation. The interference in these processes results in reduced expression and function of membrane-bound molecules, which play important roles in the initiation and effector function of the immune response. Finally, we discuss the potential role of statins in the treatment of neuroinflammatory diseases.
机译:他汀类药物由于其降脂作用而主要用于治疗高胆固醇血症,也可能具有许多免疫调节特性。他汀类药物通过抑制HMG-CoA还原酶活性来干扰甲羟戊酸途径,从而影响蛋白质的异戊二烯化和胆固醇的生物合成。他汀类药物除了降低血液中的胆固醇水平外,还抑制促炎性细胞因子的产生并降低几种免疫调节分子的膜表达,包括主要的组织相容性复合物II类(MHC-II)分子。在这篇综述中,我们讨论了他汀类药物的假定免疫调节作用以及辛伐他汀减少几种细胞类型上MHC-II分子的膜表达的机制,重点是破坏了运输和浓缩MHC的含胆固醇微域或脂质筏的破坏。 -II分子进入细胞表面。因为糖基磷脂酰肌醇(GPI)连接的蛋白质通常是生化定义的脂质筏的特征成分,并且依赖这些含胆固醇囊泡的完整性在细胞表面上转运和发挥作用,所以我们认为他汀类药物还可以通过破坏这些囊泡来实现。影响其他免疫调节分子的表达。另外,我们还认为他汀类药物通过干扰蛋白质异戊二烯基化来抑制各种蛋白质的激活和细胞内运输。在这些过程中的干扰导致膜结合分子的表达和功能降低,这在免疫应答的启动和效应子功能中起重要作用。最后,我们讨论了他汀类药物在神经炎性疾病治疗中的潜在作用。

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