FK-506-SENSITIVE AND CSA-SENSITIVE ACTIVATION OF THE INTERLEUKIN-2 PROMOTER BY CALCINEURIN
FK-506-SENSITIVE AND CSA-SENSITIVE ACTIVATION OF THE INTERLEUKIN-2 PROMOTER BY CALCINEURIN
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DOI：
10.1038/357692a0
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发表时间：
1992-06-25
期刊：
影响因子：
64.8
通讯作者：
ONEILL, EA
中科院分区：
文献类型：
--
作者：
OKEEFE, SJ;TAMURA, J;ONEILL, EA
t细胞受体（TCR）的抗原识别启动了包括淋巴因子基因转录1，特别是白细胞介素-2在内的事件，导致t细胞活化。免疫抑制药物环孢素A （CsA）和FK-506通过抑制诱导白细胞介素-2转录所需的Ca2+依赖性事件2来阻止t细胞增殖。FK-506或CsA复合物及其各自的细胞内结合蛋白在体外抑制钙调素依赖性蛋白磷酸酶钙调神经磷酸酶3。这一观察结果与免疫抑制或药物毒性的药理学相关性尚不确定。钙调磷酸酶虽然存在于淋巴细胞中，但在tcr介导的淋巴因子基因激活或一般的转录调节中并不涉及。在这里，我们报道了钙调磷酸酶催化亚基的转染增加了免疫抑制剂FK-506和CsA的50%抑制浓度（IC50），并且突变亚基与phorbol酯单独协同作用，以药物敏感的方式激活白介素-2启动子。这些结果表明钙调磷酸酶是TCR信号转导途径的一个组成部分，它在白介素-2启动子的药物敏感激活中发挥作用。
ANTIGEN recognition by the T-cell receptor (TCR) initiates events including lymphokine gene transcription 1, particularly interleukin-2, that lead to T-cell activation. The immunosuppressive drugs, cyclosporin A (CsA) and FK-506, prevent T-cell proliferation by inhibiting a Ca2+-dependent event required for induction of interleukin-2 transcription 2. Complexes of FK-506 or CsA and their respective intracellular binding proteins inhibit the calmodulin-dependent protein phosphatase, calcineurin, in vitro 3. The pharmacological relevance of this observation to immunosuppression or drug toxicity is undetermined. Calcineurin, although present in lymphocytes 4, has not been implicated in TCR-mediated activation of lymphokine genes or in transcriptional regulation in general. Here we report that transfection of a calcineurin catalytic subunit increases the 50% inhibitory concentration (IC50) of the immunosuppressants FK-506 and CsA, and that a mutant subunit acts in synergy with phorbol ester alone to activate the interleukin-2 promoter in a drug-sensitive manner. These results implicate calcineurin as a component of the TCR signal transduction pathway by demonstrating its role in the drug-sensitive activation of the interleukin-2 promoter.