Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325006, China.
Department of Gastroenterology, The First Hospital of Peking University, BeiJing 100032, China.
Toxicol Appl Pharmacol. 2022 Jan 1;434:115795. doi: 10.1016/j.taap.2021.115795. Epub 2021 Nov 12.
A chronic liver disease named autoimmune hepatitis (AIH) will carry elevated levels of inflammatory cytokines, but there is currently no effective treatment to cure it. Histone deacetylase 3 (HDAC3) takes an important position in regulating the expression of inflammatory genes. Nimbolide (NIB) is a limonoid extracted from the neem tree (Azadirachta indica) that has been found to be effective against many diseases, including cancer, scleroderma, and acute respiratory distress syndrome. Here, we investigated the protective effect of nimbolide on AIH liver. Mice and AML12 cells were employed to establish AIH model with liver antigen S100 and cell injury model of LPS, and then treated with different concentrations of nimbolide. After the successful establishment of the animal model and cell model, inflammatory cytokines of IL-1β, IL-6 and TNF-α as well as cellular signaling related to inflammation such as STAT3, IκB-α and NF-κB were examined. We observed for the first time about nimbolide can effectively inhibit inflammation in AIH mice's liver and AML12 cells by inhibiting HDAC3 expression. HDAC3 knocked down by siRNA in cells can also effectively alleviate the inflammation in AML12 cells, further confirming that HDAC3 plays an important role in the inflammation of liver cells. These results suggest nimbolide could be a potential new treatment for autoimmune hepatitis, and HDAC3 may become a new target for autoimmune hepatitis.
一种名为自身免疫性肝炎（AIH）的慢性肝病会导致炎症细胞因子水平升高，但目前尚无有效的治疗方法来治愈它。组蛋白去乙酰化酶 3（HDAC3）在调节炎症基因的表达中起着重要作用。印苦楝素（NIB）是从印楝树（印度楝）中提取的一种柠檬苦素，已被发现对许多疾病有效，包括癌症、硬皮病和急性呼吸窘迫综合征。在这里，我们研究了印苦楝素对 AIH 肝脏的保护作用。使用小鼠和 AML12 细胞建立了带有肝抗原 S100 的 AIH 模型和 LPS 细胞损伤模型，并使用不同浓度的印苦楝素进行处理。在成功建立动物模型和细胞模型后，检测了炎症细胞因子 IL-1β、IL-6 和 TNF-α 以及与炎症相关的细胞信号转导，如 STAT3、IκB-α 和 NF-κB。我们首次观察到印苦楝素可以通过抑制 HDAC3 的表达有效抑制 AIH 小鼠肝脏和 AML12 细胞的炎症。细胞中用 siRNA 敲低 HDAC3 也可以有效减轻 AML12 细胞的炎症，进一步证实 HDAC3 在肝细胞炎症中发挥重要作用。这些结果表明印苦楝素可能成为治疗自身免疫性肝炎的一种新的潜在药物，HDAC3 可能成为自身免疫性肝炎的一个新靶点。
