Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Front Immunol. 2021 Feb 2;11:625542. doi: 10.3389/fimmu.2020.625542. eCollection 2020.
CREB binding protein (CBP), a transcriptional coactivator and acetyltransferase, is involved in the pathogenesis of inflammation-related diseases. High mobility group box-1 protein (HMGB1) is a critical mediator of lethal sepsis, which has prompted investigation for the development of new treatment for inflammation. Here, we report that the potent and selective inhibition of CBP bromodomain by SGC-CBP30 blocks HMGB1-mediated inflammatory responses and . Our data suggest that CBP bromodomain inhibition suppresses LPS-induced expression and release of HMGB1, when the inhibitor was given 8 h post LPS stimulation; moreover, CBP bromodomain inhibition attenuated pro-inflammatory activity of HMGB1. Furthermore, our findings provide evidence that SGC-CBP30 down-regulated rhHMGB1-induced activation of MAPKs and NF-κB signaling by triggering the reactivation of protein phosphatase 2A (PP2A) and the stabilization of MAPK phosphatase 1 (MKP-1). Collectively, these results suggest that CBP bromodomain could serve as a candidate therapeutic target for the treatment of lethal sepsis inhibiting LPS-induced expression and release of HMGB1 and suppressing the pro-inflammatory activity of HMGB1.
CREB 结合蛋白（CBP）是一种转录共激活因子和乙酰转移酶，参与炎症相关疾病的发病机制。高迁移率族蛋白 B1（HMGB1）是致命性败血症的关键介质，这促使人们研究开发新的炎症治疗方法。在这里，我们报告说，CBP 溴结构域的强效和选择性抑制剂 SGC-CBP30 可阻断 HMGB1 介导的炎症反应。我们的数据表明，当抑制剂在 LPS 刺激后 8 小时给予时，CBP 溴结构域抑制可抑制 LPS 诱导的 HMGB1 的表达和释放；此外，CBP 溴结构域抑制可减弱 HMGB1 的促炎活性。此外，我们的研究结果提供了证据，表明 SGC-CBP30 通过触发蛋白磷酸酶 2A（PP2A）的再激活和丝裂原活化蛋白激酶磷酸酶 1（MKP-1）的稳定，下调 rhHMGB1 诱导的 MAPK 和 NF-κB 信号通路的激活。综上所述，这些结果表明，CBP 溴结构域可作为治疗致命性败血症的候选治疗靶点，通过抑制 LPS 诱导的 HMGB1 的表达和释放，并抑制 HMGB1 的促炎活性。
