Lu Jun, Sun Haijing, Wang Xiuli, Liu Chunyan, Xu Xin, Li Fen, Huang Baiqu
Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
Cytokine. 2005 Jul 7;31(1):46-51. doi: 10.1016/j.cyto.2005.03.001.
Interleukin-12 (IL-12) is a heterodimeric cytokine produced by macrophages in response to intracellular pathogens. The importance of IL-12 in generation of Th1 response against human pathogens has been characterized. The coactivator p300 is an important histone acetyltransferase (HAT) and has been implicated in the regulation of many genes. Histone deacetylases (HDACs) regulate gene transcription through deacetylation of histones. Whether the reversible histone acetylation/deacetylation modification participates in the regulation of IL-12 p40 transcription expression has not been investigated before. In this study, we analyzed the roles of HDAC1 and p300 in the regulation of human IL-12 p40. Co-transfection studies showed that HDAC1 had a repressing effect on the activity of IL-12 p40 promoter. Contrarily, p300 was able to reinforce the C/EBPbeta-mediated activation of IL-12 p40 and it counteracted the HDAC1-mediated repression of the IL-12 promoter. Chromatin immunoprecipitation tests (ChIP) revealed that p300 had a stimulating effect on the acetylation of the histone H3 at IL-12 p40 promoter. In addition, we showed that p300 had a physical interaction with C/EBPbeta and can enhance acetylation of C/EBPbeta. Data presented in this paper indicate that the reversible histone acetylation/deacetylation modification plays an important role in the transcriptional regulation of IL-12.
白细胞介素-12（IL-12）是巨噬细胞在响应细胞内病原体时产生的一种异源二聚体细胞因子。IL-12在针对人类病原体的Th1反应产生中的重要性已得到明确。共激活因子p300是一种重要的组蛋白乙酰转移酶（HAT），并参与了许多基因的调控。组蛋白去乙酰化酶（HDAC）通过组蛋白的去乙酰化作用来调节基因转录。此前尚未研究可逆的组蛋白乙酰化/去乙酰化修饰是否参与IL-12 p40转录表达的调控。在本研究中，我们分析了HDAC1和p300在人类IL-12 p40调控中的作用。共转染研究表明，HDAC1对IL-12 p40启动子的活性具有抑制作用。相反，p300能够增强C/EBPβ介导的IL-12 p40激活，并抵消HDAC1介导的IL-12启动子抑制。染色质免疫沉淀试验（ChIP）显示，p300对IL-12 p40启动子处组蛋白H3的乙酰化具有刺激作用。此外，我们发现p300与C/EBPβ存在物理相互作用，并能增强C/EBPβ的乙酰化。本文提供的数据表明，可逆的组蛋白乙酰化/去乙酰化修饰在IL-12的转录调控中起重要作用。
