Zhang Fangcheng, Xu Ruqin, Chai Renjie, Xu Qiong, Liu Mingke, Chen Xuke, Chen Xiaohua, Kong Tianyu, Zhang Chongyu, Liu Shi-Ming, Zhang Zhenhui, Liu Ningning
Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Department of Critical Care Medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Front Mol Biosci. 2020 Apr 22;7:49. doi: 10.3389/fmolb.2020.00049. eCollection 2020.
b-AP15 is a deubiquitinase (DUB) inhibitor of 19S proteasomes, which in turn targets ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14). Nuclear factor kappa B (NF-κB) is closely linked to cellular response in macrophages when the organism is in the state of microbial infection, and it acts as a vital part in the mechanism of inflammatory reaction. However, the molecular mechanism by which DUB inhibitors, especially b-AP15, regulates inflammation remains poorly understood. This study aimed to investigate the relationship between b-AP15 and inflammation. The results showed that b-AP15 treatment significantly reduced the amounts of inflammatory indicators, such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in lipopolysaccharide (LPS)-stimulated THP-1 and macrophages. Meanwhile, similar results were obtained from experiments. In addition, b-AP15 also significantly improved the survival rate of sepsis mouse via high-density LPS mediation. Furthermore, b-AP15 also inhibited the ERK1/2 and JNK phosphorylation, increased IκBα levels, and inhibited NF-κB p65 by removing them from the cytoplasm into the nucleus. All these findings suggested that b-AP15 has anti-inflammatory action and acts as a potential neoteric target drug for treating microbial infection.
b-AP15是19S蛋白酶体的去泛素化酶（DUB）抑制剂，其作用靶点为泛素C末端水解酶5（UCHL5）和泛素特异性肽酶14（USP14）。当机体处于微生物感染状态时，核因子κB（NF-κB）与巨噬细胞中的细胞反应密切相关，并且在炎症反应机制中起重要作用。然而，DUB抑制剂，尤其是b-AP15调节炎症的分子机制仍知之甚少。本研究旨在探讨b-AP15与炎症之间的关系。结果表明，b-AP15处理显著降低了脂多糖（LPS）刺激的THP-1细胞和巨噬细胞中炎症指标的含量，如肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6）。同时，在实验中也得到了类似的结果。此外，b-AP15还通过高密度LPS介导显著提高了脓毒症小鼠的存活率。此外，b-AP15还抑制ERK1/2和JNK的磷酸化，增加IκBα水平，并通过将NF-κB p65从细胞质转运到细胞核来抑制它。所有这些发现表明，b-AP15具有抗炎作用，是一种治疗微生物感染的潜在新型靶向药物。
