cAMP-induced interleukin-10 promoter activation depends on CCAAT/enhancer-binding protein expression and monocytic differentiation
cAMP-induced interleukin-10 promoter activation depends on CCAAT/enhancer-binding protein expression and monocytic differentiation
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DOI：
10.1074/jbc.m207448200
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发表时间：
2003-02-21
影响因子：
4.8
通讯作者：
Platzer, C
中科院分区：
文献类型：
--
作者：
Brenner, S;Prösch, S;Platzer, C
炎症和应激反应过程中各种刺激对单核细胞中白细胞介素（IL-10）转录调节的分子机制尚不完全清楚。最近，我们提供的证据表明，应激诱导的单核细胞中IL-10启动子激活是由儿茶酚胺通过cAMP依赖性信号通路介导的，包括CREB/ATF（cAMP响应元件结合蛋白/激活转录） 因子）与两个 CRE 基序结合。然而，这些位点的突变仅使 cAMP 反应性降低了 50%，这表明其他转录因子和元件在人类 IL-10 启动子的 cAMP 依赖性调节中发挥着作用。在这里，我们分析了这样一种因子 C/EBP 在骨髓单核细胞来源的两种细胞系 THP-1 和 HL-60 中的功能作用，已知这两种细胞系的分化状态和分化状态不同。 C/EBP 蛋白质含量。我们表明基础以及 cAMP 刺激的 IL-10 转录水平取决于 C/EBPα 和β 的表达及其与启动子/增强子区域中三个基序的结合。 C/EBP5 基序位于 TATA-box 和翻译起始点之间，对于 C/EBP 介导的组成型和大多数 cAMP 刺激的表达至关重要，因为其突变几乎 消除了 IL-10 启动子活性。我们的结果表明，相对于 CREB/ATF，C/EBP 转录因子在组织特异性和分化依赖性 IL-10 转录中起主导作用。
The molecular mechanisms underlying the regulation of interleukin (IL-10 transcription in monocytic cells by various stimuli during inflammation and the stress reaction are not fully understood. Recently, we provided evidence that stress-induced IL-10 promoter activation in monocytic cells is mediated by catecholamines via a cAMP-dependent signaling pathway including CREB/ ATF (cAMP-responsive element binding protein/activating transcription factor) binding to two CRE motifs. However, the mutation of these sites diminished cAMP responsiveness by only 50%, suggesting a role for additional transcription factors and elements in the cAMP-dependent regulation of the human IL-10 promoter. Here, we analyze the functional role of one such factor, C/EBP, in two cell lines of myelomonocytic origin, THP-1 and HL-60, which are known to differ in their differentiation status and C/EBP protein content. We show that the level of basal as well as cAMP-stimulated IL-10 transcription depends on the expression of C/EBPalpha and beta and their binding to three motifs in the promoter/enhancer region. The C/EBP5 motif, which is located between the TATA-box and the translation start point, is essential for the C/EBP-mediated constitutive and most of the cAMP-stimulated expression as its mutation nearly abolished IL-10 promoter activity. Our results suggest a dominant role of C/EBP transcription factors relative to CREB/ATF in tissue-specific and differentiation-dependent IL-10 transcription.