Huang Huimin, Li Haidi, Chen Xin, Yang Yang, Li Xiaofeng, Li Wanxia, Huang Cheng, Meng Xiaoming, Zhang Lei, Li Jun
The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, China; Institute for Liver Diseases of Anhui Medical University, China.
The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, China; Institute for Liver Diseases of Anhui Medical University, China.
Toxicol Appl Pharmacol. 2017 Aug 1;328:34-45. doi: 10.1016/j.taap.2017.05.005. Epub 2017 May 11.
Acute liver injury (ALI) is characteristic of abrupt hepatic dysfunction and inflammatory response. Activaion of Kupffer cells (KCs) plays a central role in the pathogenesis of ALI. Since the High Mobility Group A protein2 (HMGA2) occurs as a driver at critical stage of hepatocellular carcinoma, herein, we investigated the role of HMGA2 in macrophage activation during ALI. Our study found that the expression of HMGA2 decreased dramatically both in KCs isolated from the liver in mice with ALI and in LPS-induced RAW264.7 cell lines. Moreover, loss- and gain-of-function studies suggested that HMGA2 could enhance the expression of pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β. These results indicated that HMGA2 may play an essential role in macrophage activation during ALI. Additionally, our results showed the expression of HMGA2 was up-regulated when LPS-induced RAW264.7 cells were treated with 5-aza-2-deoxycytidine. Furthermore, silencing of DNMT1, DNMT3a, DNMT3b could respectively prevent the down-expression of HMGA2 in LPS-induced RAW264.7 cells. In conclusion, HMGA2 promotes the release of pro-inflammatory cytokines through NF-κB pathway, and the dysregulation of HMGA2 may involve with hypermethylation.
急性肝损伤（ALI）的特征是肝脏功能突然出现障碍以及炎症反应。库普弗细胞（KCs）的激活在ALI的发病机制中起核心作用。由于高迁移率族蛋白A2（HMGA2）在肝细胞癌的关键阶段作为驱动因子出现，因此，我们在此研究了HMGA2在ALI期间巨噬细胞激活中的作用。我们的研究发现，在从患有ALI的小鼠肝脏中分离出的KCs以及脂多糖（LPS）诱导的RAW264.7细胞系中，HMGA2的表达均显著降低。此外，功能缺失和功能获得研究表明，HMGA2可以增强包括肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）在内的促炎细胞因子的表达。这些结果表明，HMGA2可能在ALI期间巨噬细胞激活中起重要作用。此外，我们的结果显示，当用5-氮杂-2'-脱氧胞苷处理LPS诱导的RAW264.7细胞时，HMGA2的表达上调。此外，沉默DNA甲基转移酶1（DNMT1）、DNA甲基转移酶3a（DNMT3a）、DNA甲基转移酶3b（DNMT3b）可分别阻止LPS诱导的RAW264.7细胞中HMGA2的下调表达。总之，HMGA2通过核因子-κB（NF-κB）途径促进促炎细胞因子的释放，并且HMGA2的失调可能与高甲基化有关。
