THE ACTIONS OF CYCLOSPORINE-A AND FK506 SUGGEST A NOVEL STEP IN THE ACTIVATION OF LYMPHOCYTES-T
THE ACTIONS OF CYCLOSPORINE-A AND FK506 SUGGEST A NOVEL STEP IN THE ACTIVATION OF LYMPHOCYTES-T
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DOI：
10.1002/j.1460-2075.1990.tb07893.x
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发表时间：
1990-12-01
期刊：
影响因子：
11.4
通讯作者：
HERZENBERG, LA
中科院分区：
文献类型：
--
作者：
MATTILA, PS;ULLMAN, KS;HERZENBERG, LA
环孢素 A 和 FK506 是免疫抑制化合物，对 T 淋巴细胞产生的几种淋巴因子的表达具有类似的抑制作用。 尽管它们的作用相似，但这些药物分别与两种不同的胞质蛋白（亲环蛋白和 FKBP）结合，这提出了它们具有不同作用模式的可能性。使用可以容易地测量由特定转录因子控制的mRNA产生的构建体，我们发现环孢菌素A和FK506完全抑制由NF-AT、NFIL2A、NFIL2b激活的转录，并部分抑制由NF-κ-B激活的转录。环孢素 A 和 FK506 仅抑制依赖于 Ca2+ 动员的转录激活。然而，环孢菌素 A 和 FK506 并不抑制 c-fos mRNA 的 Ca2+ 动员依赖性表达，表明只有 Ca2+ 调节的信号通路子集对这些药物敏感。此外，我们没有观察到环孢菌素 A 和 FK506 对六种不同转录因子的作用之间存在任何定性差异，这表明这些药物可能会干扰调节多种转录因子的新型 Ca2+ 依赖性步骤的活性。
Cyclosporin A and FK506 are immunosuppressive compounds that have similar inhibitory effects on the expression of several lymphokines produced by T lymphocytes. Despite their similar effects the drugs bind to two different cytosolic proteins, cyclophilin and FKBP respectively, which raises the possibility that they have different modes of action. Using constructs in which mRNA production controlled by specific transcription factor could be readily measured we found that both cyclosporin A and FK506 completely inhibited transcription activated by NF-AT, NFIL2 A, NFIL2 b and partially inhibited transcription activated by NF-kappa-B. Cyclosporin A and FK506 inhibited only transcriptional activation that was dependent on Ca2+ mobilization. However, cyclosporin A and FK506 did not inhibit Ca2+ mobilization dependent expression of c-fos mRNA indicating that only subset of signalling pathways regulated by Ca2+ is sensitive to these drugs. Furthermore, we did not observe any qualitative differences between the effect of cyclosporin A anf FK506 on six different transcription factors which suggests that these drugs may interfere with the activity of a novel Ca2+ dependent step that regulates several transcription factors.