Park Eun J, Kim Young M, Kim Hye J, Chang Ki C
Department of Pharmacology Institute of Health Sciences College of Medicine Gyeongsang National University Jinju Korea.
FEBS Open Bio. 2018 Jun 5;8(7):1119-1126. doi: 10.1002/2211-5463.12456. eCollection 2018 Jul.
High mobility group box 1 (HMGB1) has been proposed as crucial in the pathogenesis of many diseases including sepsis. Acetylation of HMGB1 prevents its entry into the nucleus and leads to its secretion from the cell where it can trigger inflammation. We hypothesized that histone deacetylase 4 (HDAC4) controls the acetylation of HMGB1 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells via the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. The results showed that LPS treatment promoted the degradation of HDAC4 in a proteasome-dependent manner, which led to HMGB1 acetylation. In LPS-activated RAW264.7 cells, treatment with TAK-242 (a toll like receptor 4 inhibitor) and pyridone 6 (a JAK inhibitor) significantly inhibited HDAC4 degradation and acetylation of HMGB1, and thus prevented secretion of HMGB1. Decreased phosphorylation of STAT1 was also observed. Interestingly, HDAC4 overexpression significantly prevented the acetylation and secretion of HMGB1 in both RAW264.7 cells and isolated murine peritoneal macrophages. We conclude that HDAC4 might be a useful target for the treatment of sepsis.
高迁移率族蛋白B1（HMGB1）被认为在包括脓毒症在内的多种疾病发病机制中起关键作用。HMGB1的乙酰化可阻止其进入细胞核，并导致其从细胞分泌，进而引发炎症。我们推测组蛋白去乙酰化酶4（HDAC4）通过Janus激酶（JAK）/信号转导及转录激活因子（STAT）途径调控脂多糖（LPS）刺激的RAW264.7细胞中HMGB1的乙酰化。结果显示，LPS处理以蛋白酶体依赖的方式促进HDAC4降解，进而导致HMGB1乙酰化。在LPS激活的RAW264.7细胞中，用TAK-242（一种Toll样受体4抑制剂）和吡啶酮6（一种JAK抑制剂）处理可显著抑制HDAC4降解及HMGB1乙酰化，从而阻止HMGB1分泌。同时还观察到STAT1磷酸化水平降低。有趣的是，HDAC4过表达显著阻止了RAW264.7细胞和分离的小鼠腹腔巨噬细胞中HMGB1的乙酰化及分泌。我们得出结论，HDAC4可能是治疗脓毒症的一个有效靶点。
