CALCINEURIN PHOSPHATASE-ACTIVITY IN LYMPHOCYTES-T IS INHIBITED BY FK-506 AND CYCLOSPORINE-A
CALCINEURIN PHOSPHATASE-ACTIVITY IN LYMPHOCYTES-T IS INHIBITED BY FK-506 AND CYCLOSPORINE-A
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DOI：
10.1073/pnas.89.9.3686
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发表时间：
1992-05-01
影响因子：
11.1
通讯作者：
BURAKOFF, SJ
中科院分区：
文献类型：
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作者：
FRUMAN, DA;KLEE, CB;BURAKOFF, SJ
免疫抑制剂环孢菌素A(CsA)和FK 506结合不同家族的胞内蛋白(免疫亲和素)，称为亲环素和FK 506结合蛋白(FKBP)。最近的研究表明，在体外，CsA-亲环素和FK506-FKBP-12的络合物能结合并抑制钙调神经磷酸酶(一种钙依赖的丝氨酸/苏氨酸磷酸酶)的活性。我们研究了药物治疗对T淋巴细胞磷酸酶活性的影响。钙调神经磷酸酶在T细胞中表达，其活性可以在细胞裂解产物中测量。CsA和FK506都能在抑制激活T细胞产生白介素2的药物浓度下特异性地抑制细胞钙调神经磷酸酶。雷帕霉素与FKBPs结合，但表现出不同于FK 506的生物学活性，对钙调神经磷酸酶活性没有影响。此外，过量的雷帕霉素明显通过取代FKBP中的FK 506而阻止FK 506的作用。这些结果表明，钙调神经磷酸酶是体内药物-免疫亲和素复合体的靶标，并确立了钙调神经磷酸酶在T细胞激活中的生理作用。
The immunosuppressive agents cyclosporin A (CsA) and FK 506 bind to distinct families of intracellular proteins (immunophilins) termed cyclophilins and FK 506-binding proteins (FKBPs). Recently, it has been shown that, in vitro, the complexes of CsA-cyclophilin and FK 506-FKBP-12 bind to and inhibit the activity of calcineurin, a calcium-dependent serine/threonine phosphatase. We have investigated the effects of drug treatment on phosphatase activity in T lymphocytes. Calcineurin is expressed in T cells, and its activity can be measured in cell lysates. Both CsA and FK 506 specifically inhibit cellular calcineurin at drug concentrations that inhibit interleukin 2 production in activated T cells. Rapamycin, which binds to FKBPs but exhibits different biological activities than FK 506, has no effect on calcineurin activity. Furthermore, excess concentrations of rapamycin prevent the effects of FK 506, apparently by displacing FK 506 from FKBPs. These results show that calcineurin is a target of drug-immunophilin complexes in vivo and establish a physiological role for calcineurin in T-cell activation.