Russell R G, Graveley R, Coxon F, Skjodt H, Del Pozo E, Elford P, Mackenzie A
Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, UK.
Scand J Rheumatol Suppl. 1992;95:9-18. doi: 10.3109/03009749209101478.
Cyclosporin A is an established immunomodulatory agent with an increasing number of clinical applications. Although its precise mechanisms of action remain elusive, one of the most important known properties of CyA is its ability to inhibit the production of cytokines involved in the regulation of T-cell activation. In particular, CyA inhibits de novo synthesis of interleukin 2(IL-2), the major cytokine involved in T-cell proliferation, as well as other cytokines, probably at the level of gene transcription, as shown by the suppression of mRNA levels in activated T-cells. Although the major actions of CyA are on T-cells, there is some evidence for possible direct effects on other cell types e.g. B-cells, macrophages and, from our own work, on bone and cartilage cells. Cyclosporin A is thought to enter cells and to bind to cyclophilins, which are members of a family of high-affinity cyclosporin A-binding proteins, now known as immunophilins. The binding of cyclosporins to such proteins appears to be closely linked to the immunosuppressive action of cyclosporins. The immunophilins possess enzyme activity, ie. peptidyl-prolyl cis-trans isomerase, also known as rotamase, which can regulate protein folding, and may therefore alter the functional state of many cell proteins. Cyclosporin A blocks peptidyl-prolyl cis-trans isomerase activity but it is not clear whether this plays a part in its selective inhibition of cytokine-gene transcription. Moreover, the ubiquitous presence of cyclophilins and immunophilins raises the question of why cyclosporin A has its apparent major effects only on T-cells. Recent proposals regarding the intracellular mode of action of CyA suggest that it interacts with cyclophilin and other regulatory proteins including calmodulin and calcineurin, which is a serine/threonine phosphatase, and thereby affects the functional state of key regulators of gene transcription in its target cells. The effects of CyA on T-cells and directly or indirectly on connective tissue cells, including bone, cartilage and synovial cells, which all can produce a range of cytokines, are of interest in relation to the tissue changes that occur in inflammatory diseases, such as rheumatoid arthritis. Thus, for example, cyclosporin A inhibits in vitro the bone resorbing activity of interleukin 1, 1,25-dihydroxy-vitamin D3, parathyroid hormone and prostaglandin E2 by apparently non-T-cell effects, while in vivo protects against bone and cartilage loss in adjuvant arthritis. More needs to be known about the direct and indirect modulation of cytokine production by cyclosporin A in connective tissues, in order to understand its potential value in clinical disorders.
环孢素A是一种成熟的免疫调节剂，临床应用日益增多。尽管其确切作用机制尚不清楚，但环孢素A最重要的已知特性之一是其能够抑制参与T细胞活化调节的细胞因子的产生。特别是，环孢素A抑制白细胞介素2（IL-2）的从头合成，IL-2是参与T细胞增殖的主要细胞因子，以及其他细胞因子，可能是在基因转录水平，这已通过活化T细胞中mRNA水平的抑制得到证明。尽管环孢素A的主要作用是作用于T细胞，但有一些证据表明它可能对其他细胞类型有直接影响，例如B细胞、巨噬细胞，以及根据我们自己的研究，对骨细胞和软骨细胞也有影响。环孢素A被认为进入细胞并与亲环蛋白结合，亲环蛋白是一类高亲和力的环孢素A结合蛋白家族的成员，现在被称为亲免素。环孢素与这类蛋白质的结合似乎与环孢素的免疫抑制作用密切相关。亲免素具有酶活性，即肽基脯氨酰顺反异构酶，也称为旋转异构酶，它可以调节蛋白质折叠，因此可能改变许多细胞蛋白质的功能状态。环孢素A阻断肽基脯氨酰顺反异构酶的活性，但尚不清楚这是否在其对细胞因子基因转录的选择性抑制中起作用。此外，亲环蛋白和亲免素的普遍存在提出了一个问题，即为什么环孢素A仅对T细胞有明显的主要作用。最近关于环孢素A细胞内作用方式的提议表明，它与亲环蛋白和其他调节蛋白相互作用，包括钙调蛋白和钙神经素，钙神经素是一种丝氨酸/苏氨酸磷酸酶，从而影响其靶细胞中基因转录关键调节因子的功能状态。环孢素A对T细胞以及直接或间接对结缔组织细胞（包括骨细胞、软骨细胞和滑膜细胞，这些细胞都能产生一系列细胞因子）的作用，与类风湿关节炎等炎症性疾病中发生的组织变化有关，是令人感兴趣的。因此，例如，环孢素A在体外通过明显的非T细胞效应抑制白细胞介素1、1,25-二羟基维生素D3、甲状旁腺激素和前列腺素E2的骨吸收活性，而在体内可预防佐剂性关节炎中的骨和软骨丢失。为了了解其在临床疾病中的潜在价值，需要更多地了解环孢素A对结缔组织中细胞因子产生的直接和间接调节作用。
