Halili Maria A, Andrews Melanie R, Sweet Matthew J, Fairlie David P
Institute for Molecular Bioscience, The University of Queensland, Qld 4072, Australia.
Curr Top Med Chem. 2009;9(3):309-19. doi: 10.2174/156802609788085250.
Lysine acetylation is becoming increasingly appreciated as a key post-translational modification in the endogenous regulation of protein function. The so-called histone acetyl transferases (HATs) and histone deacetylases (HDACs), best known for their roles in controlling chromatin remodeling via histone acetylation/deacetylation, are now known to modify a large number of non-histone proteins to control diverse cell processes. In relation to inflammation, acetylation modulates the activity or function of cytokine receptors, nuclear hormone receptors, intracellular signaling molecules and transcription factors. Small molecule inhibitors of HDACs have been found to trigger both pro- and anti-inflammatory effects in a range of inflammation-relevant cell types. Although their inflammatory profiles have only just begun to be elucidated, some HDAC inhibitors are already showing therapeutic promise in animal models of inflammatory diseases such as arthritis, inflammatory bowel diseases, septic shock, ischemia-reperfusion injury, airways inflammation and asthma, diabetes, age-related macular degeneration, cardiovascular diseases, multiple sclerosis and other CNS and neurodegenerative diseases. This article describes those HDAC inhibitors which have been most examined to date for their potentially beneficial effects on inflammatory cells or in animal models of inflammatory disease.
赖氨酸乙酰化作为蛋白质功能内源性调控中的一种关键翻译后修饰，正日益受到重视。所谓的组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs），最初因通过组蛋白乙酰化/去乙酰化控制染色质重塑而闻名，现在已知它们可修饰大量非组蛋白以控制多种细胞过程。在炎症方面，乙酰化可调节细胞因子受体、核激素受体、细胞内信号分子和转录因子的活性或功能。已发现HDAC的小分子抑制剂在一系列与炎症相关的细胞类型中可引发促炎和抗炎作用。尽管它们的炎症特征才刚刚开始被阐明，但一些HDAC抑制剂已在诸如关节炎、炎症性肠病、脓毒症休克、缺血再灌注损伤、气道炎症和哮喘、糖尿病、年龄相关性黄斑变性、心血管疾病、多发性硬化症以及其他中枢神经系统和神经退行性疾病等炎症性疾病的动物模型中显示出治疗前景。本文描述了那些迄今为止在炎症细胞或炎症性疾病动物模型中其潜在有益作用已得到最多研究的HDAC抑制剂。
