Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STATS (signal transducer and activator of transcription 5) but not AP-1
Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STATS (signal transducer and activator of transcription 5) but not AP-1
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DOI：
10.1210/me.15.7.1062
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发表时间：
2001-07-01
影响因子：
--
通讯作者：
Pallardy, M
中科院分区：
文献类型：
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作者：
Biola, A;Lefebvre, P;Pallardy, M
细胞因子和糖皮质激素（GC）信号通路在免疫系统中的细胞凋亡和基因表达的调节中相互干扰。白细胞介素-2（IL-2）通过Janus激酶/信号转导子和转录激活子（Jak/STAT）和丝裂原活化蛋白激酶（MAPK）途径，分别激活STAT 5和活化蛋白-1（AP-1）转录因子，已知它们至少部分通过蛋白质-蛋白质相互作用抑制糖皮质激素受体（GR）活性。在这项工作中，我们分析了IL-2下调GC诱导的小鼠乳腺肿瘤病毒长末端重复序列（MMTV-LTR）在小鼠CTLL-2 T淋巴细胞中的反式激活的机制。突变研究表明，MMTV-LTR STAT 5结合位点（-923/-914）不是IL-2介导的抑制所需的，但确定糖皮质激素反应元件（GR）和-104/+1区域都是这种阴性反应的关键元件。GC介导的MMTV-LTR启动子激活所需的转录因子的DNA结合活性以及与-104/+1区域（核因子-1，Oct-1）结合的转录因子的DNA结合活性不受IL-2处理的影响。野生型STAT 5 B的过表达增强了IL-2对MMTV-LTR活性的影响，并且STAT 5 B的显性负性形式（Y 699 F）消除了IL-2介导的MMTV-LTR抑制，而AP-1活化在该系统中没有影响。在CTLL-2细胞中观察到liganded on与STAT 5之间以STAT 5磷酸化非依赖性方式直接相互作用。核辅激活因子CBP（CREB结合蛋白）或SRC-1a（类固醇受体辅激活因子1a）的过表达不会减弱IL-2的抑制作用。我们认为，STATE抑制活性GC依赖的转录可能涉及直接相互作用的STAT 5与GR，是依赖于启动子上下文和STAT 5激活水平，并发生独立的辅激活因子水平的T细胞。
Cytokines and glucocorticoids (GCs) signaling pathways interfere with each other in the regulation of apoptosis and gene expression in the immune system. Interleukin-2 (IL-2), through the Janus kinase/signal transducers and activators of transcription (Jak/STAT) and mitogen-activated protein kinase (MAPK) pathways, activates STAT5 and activated protein-1 (AP-1) transcription factors, respectively, which are known to repress glucocorticoid receptor (GR) activity, at least in part, through protein-protein interactions. In this work, we have analyzed the mechanisms whereby IL-2 down-regulates the GC-induced transactivation of the mouse mammary tumor virus long terminal repeat (MMTV-LTR) in murine CTLL-2 T lymphocytes. Mutagenesis studies revealed that the MMTV-LTR STAT5 binding site (-923/-914) was not required for IL-2-mediated inhibition but identified both glucocorticoid response elements (GREs) and the -104/+1 region as critical elements for this negative response. The DNA binding activities of transcription factors required for GC-mediated activation of the MMTV-LTR promoter and that bind to the -104/+1 region (nuclear factor-1, Oct-1) were not affected by IL-2 treatment. Overexpression of wild-type STAT5B enhanced the effect of IL-2 on MMTV-LTR activity, and a dominant negative form of STAT5B (Y699F) abolished the IL-2-mediated MMTV-LTR inhibition, whereas AP-1 activation had no effect in this system. Direct interaction between liganded on and STAT5 was observed in CTLL-2 cells in a STAT5 phosphorylation-independent manner. Overexpression of nuclear coactivators CBP (CREB-binding protein) or SRC-1a (steroid receptor coactivator 1a) did not blunt IL-2 inhibitory effects. We suggest that the STATE-repressive activity on the GC-dependent transcription may involve direct interaction of STAT5 with GR, is dependent on the promoter context and STAT5 activation level, and occurs independently of coactivators levels in T cells.