Histone hyperacetylation is associated with amelioration of experimental colitis in mice
Histone hyperacetylation is associated with amelioration of experimental colitis in mice
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DOI：
10.4049/jimmunol.176.8.5015
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发表时间：
2006-04-15
影响因子：
4.4
通讯作者：
Siegmund, Britta
中科院分区：
文献类型：
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作者：
Glauben, Rainer;Batra, Arvind;Siegmund, Britta
组蛋白去乙酰化酶（HDAC）抑制剂正在临床前癌症试验中研究其抗增殖作用。最近的研究表明这类化合物具有抗炎作用。由于炎症性肠病与恶性肿瘤风险增加相关，因此具有抗增殖和抗炎特性的药物将具有治疗意义。选择来自不同类别的RDAC抑制剂，并评价其体外抑制细胞因子产生和诱导细胞凋亡和组蛋白乙酰化的能力。选择丙戊酸（VPA）和琥珀酰苯胺异羟肟酸（SAHA）用于进一步研究葡聚糖硫酸钠和三硝基苯磺酸诱导的小鼠结肠炎。在体外，HDAC的抑制导致细胞因子合成和细胞凋亡诱导的剂量依赖性抑制，与细胞因子抑制相比，需要更高浓度的HDAC抑制剂用于细胞凋亡诱导。口服VPA或SAHA可降低葡聚糖硫酸钠诱导的结肠炎的疾病严重程度。疾病严重程度的肉眼和组织学减轻与结肠促炎细胞因子的显著抑制相关。与观察到的有益作用平行，在VPA治疗下，炎症部位的组蛋白3乙酰化呈剂量依赖性增加。此外，SAHA以及VPA治疗导致三硝基苯磺酸诱导的结肠炎的改善，这与固有层淋巴细胞凋亡的增加有关。HDAC抑制剂通过诱导细胞凋亡和抑制促炎细胞因子，在不同的实验性结肠炎模型中显示出强烈的保护作用，从而代表了一类用于人类炎症性肠病临床研究的有前途的化合物。
Inhibitors of histone deacetylases (HDAC) are being studied for their antiproliferative effects in preclinical cancer trials. Recent studies suggest an anti-inflammatory role for this class of compounds. Because inflammatory bowel disease is associated with an increased risk of malignancies, agents with antiproliferative and anti-inflammatory properties would be of therapeutic interest. RDAC inhibitors from various classes were selected and evaluated for their in vitro capacity to suppress cytokine production and to induce apoptosis and histone acetylation. Valproic acid (VPA) and suberyolanilide hydroxamic acid (SAHA) were chosen for further studies in dextran sulfate sodium- and trinitrobenzene sulfonic acid-induced colitis in mice. In vitro, inhibition of HDAC resulted in a dose-dependent suppression of cytokine synthesis and apoptosis induction requiring higher concentrations of HDAC inhibitors for apoptosis induction compared with cytokine inhibition. Oral administration of either VPA or SAHA reduced disease severity in dextran sulfate sodium-induced colitis. The macroscopic and histologic reduction of disease severity was associated with a marked suppression of colonic proinflammatory cytokines. In parallel to the beneficial effect observed, a dose-dependent increase in histone 3 acetylation at the site of inflammation was shown under VPA treatment. Furthermore, SAHA as well as VPA treatment resulted in amelioration of trinitrobenzene sulfonic acid-induced colitis, which was associated with an increase of apoptosis of lamina propria lymphocytes. Inhibitors of HDAC reveal strong protective effects in different models of experimental colitis by inducing apoptosis and suppressing proinflammatory cytokines, thereby representing a promising class of compounds for clinical studies in human inflammatory bowel disease.