Chen Jinjing, Wang Zhen, Hu Xiangming, Chen Ruichuan, Romero-Gallo Judith, Peek Richard M, Chen Lin-Feng
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China;
Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China;
J Immunol. 2016 May 15;196(10):4132-42. doi: 10.4049/jimmunol.1502261. Epub 2016 Apr 15.
Helicobacter pylori infection causes chronic gastritis and peptic ulceration. H. pylori-initiated chronic gastritis is characterized by enhanced expression of many NF-κB-regulated inflammatory cytokines. Brd4 has emerged as an important NF-κB regulator and regulates the expression of many NF-κB-dependent inflammatory genes. In this study, we demonstrated that Brd4 was not only actively involved in H. pylori-induced inflammatory gene mRNA transcription but also H. pylori-induced inflammatory gene enhancer RNA (eRNA) synthesis. Suppression of H. pylori-induced eRNA synthesis impaired H. pylori-induced mRNA synthesis. Furthermore, H. pylori stimulated NF-κB-dependent recruitment of Brd4 to the promoters and enhancers of inflammatory genes to facilitate the RNA polymerase II-mediated eRNA and mRNA synthesis. Inhibition of Brd4 by JQ1 attenuated H. pylori-induced eRNA and mRNA synthesis for a subset of NF-κB-dependent inflammatory genes. JQ1 also inhibited H. pylori-induced interaction between Brd4 and RelA and the recruitment of Brd4 and RNA polymerase II to the promoters and enhancers of inflammatory genes. Finally, we demonstrated that JQ1 suppressed inflammatory gene expression, inflammation, and cell proliferation in H. pylori-infected mice. These studies highlight the importance of Brd4 in H. pylori-induced inflammatory gene expression and suggest that Brd4 could be a potential therapeutic target for the treatment of H. pylori-triggered inflammatory diseases and cancer.
幽门螺杆菌感染会导致慢性胃炎和消化性溃疡。幽门螺杆菌引发的慢性胃炎的特征是许多核因子κB（NF-κB）调控的炎性细胞因子表达增强。溴结构域蛋白4（Brd4）已成为一种重要的NF-κB调节因子，并调控许多NF-κB依赖性炎性基因的表达。在本研究中，我们证明Brd4不仅积极参与幽门螺杆菌诱导的炎性基因mRNA转录，还参与幽门螺杆菌诱导的炎性基因增强子RNA（eRNA）合成。抑制幽门螺杆菌诱导的eRNA合成会损害幽门螺杆菌诱导的mRNA合成。此外，幽门螺杆菌刺激NF-κB依赖性地将Brd4募集至炎性基因的启动子和增强子，以促进RNA聚合酶II介导的eRNA和mRNA合成。JQ1对Brd4的抑制作用减弱了幽门螺杆菌诱导的一部分NF-κB依赖性炎性基因的eRNA和mRNA合成。JQ1还抑制了幽门螺杆菌诱导的Brd4与RelA之间的相互作用以及Brd4和RNA聚合酶II向炎性基因启动子和增强子的募集。最后，我们证明JQ1抑制了幽门螺杆菌感染小鼠的炎性基因表达、炎症和细胞增殖。这些研究突出了Brd4在幽门螺杆菌诱导的炎性基因表达中的重要性，并表明Brd4可能是治疗幽门螺杆菌引发的炎性疾病和癌症的潜在治疗靶点。
