Fruman D A, Klee C B, Bierer B E, Burakoff S J
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Proc Natl Acad Sci U S A. 1992 May 1;89(9):3686-90. doi: 10.1073/pnas.89.9.3686.
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.
免疫抑制剂环孢素A（CsA）和FK 506与不同的细胞内蛋白质家族（亲免素）结合，这些蛋白质分别称为亲环蛋白和FK 506结合蛋白（FKBPs）。最近研究表明，在体外，CsA - 亲环蛋白复合物和FK 506 - FKBP - 12复合物能结合并抑制钙调神经磷酸酶的活性，钙调神经磷酸酶是一种钙依赖性丝氨酸/苏氨酸磷酸酶。我们研究了药物处理对T淋巴细胞中磷酸酶活性的影响。钙调神经磷酸酶在T细胞中表达，其活性可在细胞裂解物中测量。CsA和FK 506在抑制活化T细胞中白细胞介素2产生的药物浓度下，均能特异性抑制细胞中的钙调神经磷酸酶。雷帕霉素与FKBPs结合，但具有与FK 506不同的生物学活性，对钙调神经磷酸酶活性无影响。此外，过量的雷帕霉素可阻止FK 506的作用，显然是通过将FK 506从FKBPs上置换下来实现的。这些结果表明，钙调神经磷酸酶是体内药物 - 亲免素复合物的作用靶点，并确立了钙调神经磷酸酶在T细胞活化中的生理作用。
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