Clipstone N A, Crabtree G R
Beckman Center for Molecular and Genetic Medicine, Howard Hughes Medical Institute, Stanford University School of Medicine, California 94305.
Nature. 1992 Jun 25;357(6380):695-7. doi: 10.1038/357695a0.
The immunosuppressive drugs cyclosporin A (CsA) and FK506 both interfere with a Ca(2+)-sensitive T-cell signal transduction pathway, thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A) involved in lymphokine gene expression. CsA and FK506 seem to act by interaction with their cognate intracellular receptors, cyclophilin and FKBP, respectively (see ref. 11 for review). The Ca2+/calmodulin-regulated phosphatase calcineurin is a major target of drug-isomerase complexes in vitro. We have therefore tested the hypothesis that this interaction is responsible for the in vivo effects of CsA/FK506. We report here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription. These results identify calcineurin as a key enzyme in the T-cell signal transduction cascade and provide biological evidence to support the notion that the interaction of drug-isomerase complexes with calcineurin underlies the molecular basis of CsA/FK506-mediated immunosuppression.
免疫抑制药物环孢素A（CsA）和FK506均干扰一条Ca(2+)敏感的T细胞信号转导途径，从而阻止参与淋巴因子基因表达的特定转录因子（如NF-AT和NF-IL2A）的激活。CsA和FK506似乎分别通过与它们同源的细胞内受体亲环蛋白和FKBP相互作用来发挥作用（综述见参考文献11）。Ca2+/钙调蛋白调节的磷酸酶钙调神经磷酸酶是体外药物-异构酶复合物的主要靶点。因此，我们检验了这一假说，即这种相互作用是CsA/FK506体内效应的原因。我们在此报告，Jurkat细胞中钙调神经磷酸酶的过表达使其对CsA和FK506的作用更具抗性，并增强了NFAT和NFIL2A依赖的转录。这些结果确定钙调神经磷酸酶是T细胞信号转导级联反应中的关键酶，并提供了生物学证据来支持药物-异构酶复合物与钙调神经磷酸酶的相互作用是CsA/FK506介导的免疫抑制分子基础这一观点。
