Synergy between signal transducer and activator of transcription 3 and retinoic acid receptor-α in regulation of the surfactant protein B gene in the lung
Synergy between signal transducer and activator of transcription 3 and retinoic acid receptor-α in regulation of the surfactant protein B gene in the lung
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DOI：
10.1210/me.2003-0458
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发表时间：
2004-06-01
影响因子：
--
通讯作者：
Yan, C
中科院分区：
文献类型：
--
作者：
Yang, L;Lian, XM;Yan, C
在呼吸周期中，空气中的颗粒物和病原体被吸入肺部，这可引起呼吸巨噬细胞产生细胞因子和炎症反应。分泌的细胞因子影响肺表面活性物质蛋白的表达和肺内环境的稳定。在体外共培养实验中，肺泡巨噬细胞以脂多糖不依赖和依赖的方式刺激原代肺泡II型上皮细胞中人表面活性蛋白B(HSP-B)基因转录。IL-6抗体中和可阻断脂多糖依赖的巨噬细胞对HSP-B基因转录的刺激。IL-6促进肺泡II型上皮细胞和Clara细胞Y705位信号转导和转录激活因子3的磷酸化。对STAT1和STAT3功能域互换的生化分析表明，SH2结构域和DNA结合域在STAT3刺激HSP-B基因转录过程中起关键作用。谷胱甘肽-S-转移酶下拉研究确定了STAT3和维甲酸受体-α之间蛋白质相互作用所需的功能结构域。将STAT3和维甲酸受体α共转染入呼吸道上皮细胞，可协同DNA结合和转录激活HSP-B基因。为了评估STAT3的生理功能，在多西环素控制的双转基因小鼠系中，呼吸上皮细胞中显性负的STAT3过表达导致了肺气肿和高氧时动物死亡的增加。因此，IL-6/STAT3信号轴在肺表面活性物质蛋白动态平衡和呼吸系统炎症中起重要作用。
During respiratory cycles, airborne particles and pathogens are inhaled into the lung, which can cause cytokine production by respiratory macrophages and inflammatory responses. Secreted cytokines affect surfactant protein expression and homeostasis in the lung. In coculturing experiments in vitro, bronchoalveolar macrophages stimulated human surfactant protein B (hSP-B) gene transcription in primary alveolar type II epithelial cells in lipopolysaccharide-independent and -dependent ways. Neutralization by IL-6 antibody abolished lipopolysaccharide-dependent macrophage stimulation of hSP-B gene transcription. IL-6 treatment enhanced signal transducer and activator of transcription (Stat) 3 phosphorylation at Y705 in alveolar type II epithelial cells and Clara cells in vivo. Biochemical analysis of functional domain swapping between Stat1 and Stat3 identified that the SH2 domain and the DNA binding domain are critical for Stat3 stimulation of hSP-B gene transcription. Glutathione-S-transferase pull-down study determined functional domains required for protein-protein interaction between Stat3 and retinoic acid receptor-alpha. Cotransfection of Stat3 and retinoic acid receptor-alpha into respiratory epithelial cells resulted in synergistic DNA binding and transcriptional activation on the hSP-B gene. To assess Stat3 physiological function, overexpression of a dominant negative Stat3 in respiratory epithelial cells in a doxycycline-controlled double transgenic mouse line caused pulmonary emphysema and increase of animal death during hyperoxia. Therefore, the IL-6/Stat3 signaling axis plays an important role in surfactant protein homeostasis and respiratory inflammation in the lung.