Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation
Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation
复制标题
DOI：
10.1093/embo-reports/kvd090
复制
发表时间：
2000-11-01
期刊：
影响因子：
7.7
通讯作者：
Koyasu, S
中科院分区：
文献类型：
--
作者：
Matsuda, S;Shibasaki, F;Koyasu, S
环孢菌素A（CsA）和FK 506的免疫抑制作用是通过与亲免素结合介导的。在这里，我们表明，FK 506-FKBP复合物抑制JNK和p38途径的激活，在上游的丝裂原活化蛋白激酶（MAPK）激酶激酶（MAPKK-K）的水平，除了钙调神经磷酸酶-NFAT途径。A238 L是一种与亲免素结合的病毒基因产物，也能阻断两种途径的激活。相比之下，钙调磷酸酶的直接抑制剂Cabin 1和FR 901725可以抑制NFAT的激活，但不能抑制JNK或p38途径的激活。我们进一步证明了组成型活性NFAT和组成型活性MEKK 1的共表达使得Jurkat T淋巴细胞中的白细胞介素-2启动子对CsA和FK 506具有抗性，而单独表达组成型活性NFAT的Jurkat细胞仍然对CsA或FK 506敏感。因此，CsA和FK 506通过靶向JNK和p38的钙调神经磷酸酶依赖性NFAT途径和钙调神经磷酸酶非依赖性活化途径发挥其免疫抑制作用。
The immunosuppressive effects of cyclosporin A (CsA) and FK506 are mediated through binding to immunophilins. Here we show that FK506-FKBP complex suppresses the activation of JNK and p38 pathways at a level upstream of mitogen-activated protein kinase (MAPK) kinase kinase (MAPKK-K) besides the calcineurin-NFAT pathway. A238L, a viral gene product that binds to immunophilin, also blocks activation of both pathways. In contrast, direct inhibitors of calcineurin, Cabin 1 and FR901725, suppress the activation of NFAT but not the JNK or p38 pathway. We further demonstrate that coexpression of a constitutively active NFAT and a constitutively active MEKK1 renders the interleukin-2 promoter in Jurkat T lymphocytes resistant to CsA and FK506, whereas Jurkat cells expressing a constitutively active NFAT alone are still sensitive to CsA or FK506. Therefore, CsA and FK506 exert their immunosuppressive effects through targeting both the calcineurin-dependent NFAT pathway and calcineurin-independent activation pathway for JNK and p38.