Department of Medicine, the University of Louisville, Louisville, Kentucky, USA.
Am J Pathol. 2011 Aug;179(2):693-702. doi: 10.1016/j.ajpath.2011.04.006. Epub 2011 Jun 2.
Neutrophil infiltration caused by IL-8 production is a central mechanism in alcohol-induced hepatitis. This study was performed to examine if an epigenetic mechanism is involved in alcohol-induced IL-8 production. Mice were pair-fed an alcohol-containing liquid diet for 4 weeks. Alcohol exposure induced hepatitis as indicated by increased expression of keratinocyte-derived cytokine (mouse IL-8) and neutrophil infiltration. Alcohol exposure induced histone 3 hyperacetylation owing to inhibition of histone deacetylase (HDAC) in association with NF-κB activation. Cell culture studies showed that alcohol exposure induced IL-8 and cytokine-induced neutrophil chemoattractant-1 (CINC-1, rat IL-8) production in human VL-17A cells and rat H4IIEC3 cells, respectively, dependent on acetaldehyde production, oxidative stress, and zinc release. Zinc deprivation alone induced CINC-1 production and acted synergistically with lipopolysaccharide or tumor necrosis factor-α on CINC-1 production. Zinc deprivation induced histone 3 hyperacetylation at lysine 9 through suppression of HDAC activity. Zinc deprivation caused nuclear translocation of NF-κB, and reduced HDAC binding to NF-κB. Chromatin immunoprecipitation (ChIP) showed that zinc deprivation caused histone 3 hyperacetylation as well as increased NF-κB binding to the CINC-1 promoter. In conclusion, inactivation of HDAC caused by zinc deprivation is a novel mechanism underlying IL-8 up-regulation in alcoholic hepatitis.
中性粒细胞浸润是由白细胞介素-8（IL-8）产生引起的，这是酒精性肝炎的一个核心机制。本研究旨在探讨是否存在表观遗传机制参与酒精诱导的 IL-8 产生。通过给配对喂食含酒精液体饮食 4 周的小鼠来进行实验。酒精暴露会导致肝炎，表现为角蛋白细胞衍生细胞因子（小鼠 IL-8）表达增加和中性粒细胞浸润。酒精暴露会抑制组蛋白去乙酰化酶（HDAC），导致组蛋白 3 过度乙酰化，同时伴随着 NF-κB 的激活。细胞培养研究表明，酒精暴露会诱导人 VL-17A 细胞和大鼠 H4IIEC3 细胞分别产生白细胞介素-8（IL-8）和细胞因子诱导的中性粒细胞趋化因子-1（CINC-1，大鼠 IL-8），这一过程依赖于乙醛产生、氧化应激和锌释放。单独的锌剥夺会诱导 CINC-1 的产生，并且与脂多糖或肿瘤坏死因子-α协同作用于 CINC-1 的产生。锌剥夺会通过抑制 HDAC 活性导致赖氨酸 9 上的组蛋白 3 过度乙酰化。锌剥夺会导致 NF-κB 核易位，并减少 HDAC 与 NF-κB 的结合。染色质免疫沉淀（ChIP）显示，锌剥夺会导致组蛋白 3 过度乙酰化以及 NF-κB 与 CINC-1 启动子结合增加。总之，锌剥夺导致的 HDAC 失活是酒精性肝炎中 IL-8 上调的一种新机制。
