Krüger M, Schwaninger M, Blume R, Oetjen E, Knepel W
Department of Molecular Pharmacology, University of Göttingen, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Oct;356(4):433-40. doi: 10.1007/pl00005073.
The clinically important immunosuppressant drugs cyclosporin A and FK506 (tacrolimus) inhibit in T-cells calcineurin phosphatase activity and nuclear translocation of the cytosolic component of the transcription factor nuclear factor of activated T-cells (NF-ATc) that is involved in the induction of early genes during T-cell activation. This effect has been proposed to explain at least part of the immunosuppressive effect of these drugs. Previous studies in pancreatic islet cell lines have shown that cyclosporin A and FK506 through inhibition of calcineurin interfere also with the function of the transcription factor cAMP response element binding protein (CREB) that is activated by cAMP and calcium signals and binds to cAMP/calcium response elements (CRE). By transient expression of CRE-reporter genes or GAL4-CREB fusion proteins, the present study shows that inhibition of CREB/CRE-directed transcription by cyclosporin A and FK506 occurs in a great variety of cell types including in cell lines derived from tissues in which adverse effects of the immunosuppressants develop. CREB activity and CRE-mediated transcription was blocked by these drugs also in Jurkat T-cells. When taken together with recent evidence for an essential role of CREB in T-cell activation and proliferation, the present results suggest that inhibition of CREB/CRE-directed transcription may be a molecular mechanism of the immunosuppressive effect of cyclosporin A and FK506.
临床上重要的免疫抑制剂环孢素A和FK506（他克莫司）可抑制T细胞中的钙调神经磷酸酶磷酸酶活性以及转录因子活化T细胞核因子（NF-ATc）的胞质成分的核转位，NF-ATc参与T细胞活化过程中早期基因的诱导。有人提出这种作用至少可以部分解释这些药物的免疫抑制作用。先前在胰岛细胞系中的研究表明，环孢素A和FK506通过抑制钙调神经磷酸酶，也会干扰转录因子cAMP反应元件结合蛋白（CREB）的功能；CREB由cAMP和钙信号激活，并与cAMP/钙反应元件（CRE）结合。通过瞬时表达CRE报告基因或GAL4-CREB融合蛋白，本研究表明，环孢素A和FK506对CREB/CRE指导的转录的抑制作用发生在多种细胞类型中，包括来自会产生免疫抑制剂不良反应的组织所衍生的细胞系。在Jurkat T细胞中，这些药物也会阻断CREB活性和CRE介导的转录。结合最近关于CREB在T细胞活化和增殖中起重要作用的确切证据来看，目前的结果表明，抑制CREB/CRE指导的转录可能是环孢素A和FK506免疫抑制作用的分子机制。
