Emmel E A, Verweij C L, Durand D B, Higgins K M, Lacy E, Crabtree G R
Howard Hughes Medical Institute, Stanford University, CA 94305.
Science. 1989 Dec 22;246(4937):1617-20. doi: 10.1126/science.2595372.
One action of cyclosporin A thought to be central to many of its immunosuppressive effects is its ability to inhibit the early events of T lymphocyte activation such as lymphokine gene transcription in response to signals initiated at the antigen receptor. Cyclosporin A was found to specifically inhibit the appearance of DNA binding activity of NF-AT, AP-3, and to a lesser extent NF-kappa B, nuclear proteins that appear to be important in the transcriptional activation of the genes for interleukin-2 and its receptor, as well as several other lymphokines. In addition, cyclosporin A abolished the ability of the NF-AT binding site to activate a linked promoter in transfected mitogen-stimulated T lymphocytes and in lymphocytes from transgenic mice. These results indicate that cyclosporin A either directly inhibits the function of nuclear proteins critical to T lymphocyte activation or inhibits the action of a more proximal member of the signal transmission cascade leading from the antigen receptor to the nucleus.
环孢素A的一种作用被认为是其许多免疫抑制作用的核心，即它能够抑制T淋巴细胞激活的早期事件，如响应抗原受体启动的信号而发生的淋巴因子基因转录。发现环孢素A能特异性抑制NF-AT、AP-3的DNA结合活性的出现，对NF-κB的抑制作用较小，这些核蛋白似乎在白细胞介素-2及其受体以及其他几种淋巴因子的基因转录激活中起重要作用。此外，环孢素A消除了NF-AT结合位点在转染的丝裂原刺激的T淋巴细胞和转基因小鼠淋巴细胞中激活相连启动子的能力。这些结果表明，环孢素A要么直接抑制对T淋巴细胞激活至关重要的核蛋白的功能，要么抑制从抗原受体到细胞核的信号传递级联中更上游成员的作用。
