Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection
Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection
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DOI：
10.1182/blood-2010-05-284711
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发表时间：
2011-01-27
期刊：
影响因子：
20.3
通讯作者：
Calandra, Thierry
中科院分区：
文献类型：
--
作者：
Roger, Thierry;Lugrin, Jerome;Calandra, Thierry
在组蛋白乙酰转移酶和脱乙酰酶(HDAC)的调控下，组蛋白乙酰化是控制染色质结构、DNA可及性和基因表达的关键表观遗传机制。HDAC抑制剂可诱导肿瘤细胞的生长停滞、分化和凋亡，并被用作抗癌药物。在这里，我们描述了HDAC抑制剂在体外对巨噬细胞和树突状细胞的微生物感知和体内宿主对感染的防御的影响。通过全基因组芯片分析或Toll样受体激动剂刺激的巨噬细胞和树突状细胞的先天免疫反应，HDAC抑制剂下调了许多宿主防御基因的表达，包括模式识别受体、激酶、转录调节因子、细胞因子、趋化因子、生长因子和共刺激分子。HDAC抑制剂诱导Mi-2β的表达，并增强Mi-2/NuRD复合体的DNA结合活性，该复合体作为巨噬细胞细胞因子产生的转录抑制因子。在体内，HDAC抑制剂增加了对细菌和真菌感染的敏感性，但对毒性和感染性休克具有保护作用。因此，这些数据确定了HDAC抑制剂在调节先天性免疫基因的表达和宿主对微生物病原体的防御中的重要作用。(血。2011；117(4)：1205-1217)
Regulated by histone acetyltransferases and deacetylases (HDACs), histone acetylation is a key epigenetic mechanism controlling chromatin structure, DNA accessibility, and gene expression. HDAC inhibitors induce growth arrest, differentiation, and apoptosis of tumor cells and are used as anticancer agents. Here we describe the effects of HDAC inhibitors on microbial sensing by macrophages and dendritic cells in vitro and host defenses against infection in vivo. HDAC inhibitors down-regulated the expression of numerous host defense genes, including pattern recognition receptors, kinases, transcription regulators, cytokines, chemokines, growth factors, and costimulatory molecules as assessed by genome-wide microarray analyses or innate immune responses of macrophages and dendritic cells stimulated with Toll-like receptor agonists. HDAC inhibitors induced the expression of Mi-2 beta and enhanced the DNA-binding activity of the Mi-2/NuRD complex that acts as a transcriptional repressor of macrophage cytokine production. In vivo, HDAC inhibitors increased the susceptibility to bacterial and fungal infections but conferred protection against toxic and septic shock. Thus, these data identify an essential role for HDAC inhibitors in the regulation of the expression of innate immune genes and host defenses against microbial pathogens. (Blood. 2011;117(4):1205-1217)