Comparison of the properties of the CsA analogs monoacetyl CyC (o-acetyl-threonine2 cyclosporin) and methyl-alanyl CsA (N-methyl-L-alanyl6 cyclosporin); monoacetyl cyclosporin is immunosuppressive without binding to cyclophilin.
Comparison of the properties of the CsA analogs monoacetyl CyC (o-acetyl-threonine2 cyclosporin) and methyl-alanyl CsA (N-methyl-L-alanyl6 cyclosporin); monoacetyl cyclosporin is immunosuppressive without binding to cyclophilin.
复制标题
CsA 类似物单乙酰 CyC（o-乙酰基-苏氨酸2 环孢菌素）和甲基-丙氨酰 CsA（N-甲基-L-丙氨酰6 环孢菌素）的特性比较；
DOI：
10.1111/j.1365-2249.1992.tb06892.x
复制
发表时间：
1992
影响因子：
4.6
通讯作者：
Reem,GH
中科院分区：
文献类型：
--
作者：
elRouby,S;Shi,Y;Reem,GH
环孢菌素（CsA）是一种与亲环素（Cyp）结合的免疫抑制剂。Cyp结合和免疫抑制之间的关系一直受到质疑，因为CsA的类似物之一，N-甲基-L-丙氨酰6环孢菌素（甲基-atanyl CsA）与Cyp结合但不具有免疫抑制作用。我们比较了CsA、甲基丙氨酰CsA和单乙酰基苏氨酸2环孢菌素（单乙酰基CyC）的免疫抑制特性，因为单乙酰基CyC在无细胞测定中测试时不与Cyp结合，并且其免疫抑制特性尚未测试。Cyp是一种肽基脯氨酰异构酶，在人体所有组织中含量丰富，但CsA的活性主要限于抑制T细胞和胸腺细胞活化，以及神经和肾毒性，并且与异构酶的抑制无关。胸腺细胞和T细胞的活化通过核因子（NF）与IL-2启动子的NF-AT区（-285至-255）的结合来调节。我们研究了抑制结合到NF-AT区域的NF衍生自原代培养的胸腺细胞用CsA或其类似物处理。此外，我们比较了CsA及其类似物对稳定转染的Jurkat细胞系（Fgl 5）中IL-2基因表达的影响，该细胞系含有三个拷贝的NF-AT和报告酶β-半乳糖苷酶;以及对伴刀豆球蛋白A（Con A）或IL-2诱导的增殖的抑制作用。我们发现，不结合Cyp的单乙酰CyC在培养细胞中测试时，由于不同的作用机制或代谢活化，根据我们的标准具有免疫抑制作用。
Cyclosporin (CsA) is an immunosuppressant which binds to cyclophilin (Cyp). The relationship between Cyp binding and immunosuppression has been questioned since one of the analogs of CsA, N-methyl-L-alanyl6cyclosporin (methyl-atanyl CsA) binds to Cyp but is not immunosuppressive. We compared the immunosuppressive properties of CsA, methyl-alanyl CsA ando-acetyl-threonine2cyclosporin (monoacetyl CyC), since monoacetyl CyC does not bind to Cyp when tested in cell-free assays and its immunosuppressive properties had not been tested. Cyp is a peptidyl-prolyl isomerase which is abundant in all human tissues, yet the activities of CsA are mostly confined to inhibition of T cell and thymocyte activation, and to neuro- and nephro-toxicity and are independent of inhibition of the isomerase. Activation of thymocytes and of T cells is regulated by the binding of a nuclear factor(s) (NFs) to the NF-AT region (– 285 to – 255) of the IL-2 promoter. We studied inhibition of binding to the NF-AT region of NFs derived from primary cultures of thymocytes treated with CsA or its analogs. In addition, we compared the effect of CsA and its analogs on the expression of the IL-2 gene in a stably transfected Jurkat-cell line (Fgl 5) which contains three copies of NF-AT and the reporter enzyme β-galactosidase; and on inhibition of proliferation induced by concanavalin A(Con A) or IL-2. We found that monoacetyl CyC which does not bind to Cyp is immunosuppressive by our criteria when tested in cultured cells due to either a different mechanism of action or to metabolic activation.