BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation.
BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation.
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DOI：
10.4049/jimmunol.1502261
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发表时间：
2016-05-15
期刊：
影响因子：
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通讯作者：
Chen LF
中科院分区：
文献类型：
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作者：
Chen J;Wang Z;Hu X;Chen R;Romero-Gallo J;Peek RM Jr;Chen LF
H.幽门螺杆菌感染引起慢性胃炎和消化性溃疡。H.幽门螺杆菌引起的慢性胃炎的特征是许多NF-κ B调节的炎性细胞因子的表达增强。Brd 4是一种重要的NF-κB B调节因子，调节多种NF-κ B依赖性炎症基因的表达。在这项研究中，我们证明了Brd 4不仅积极参与H。pylori诱导的炎性基因mRNA转录，但H. pylori诱导的炎症基因eRNA合成。抑制H. pylori诱导的eRNA合成损害H.幽门诱导的mRNA合成。此外，H. pylori刺激NF-κ B依赖性的Brd 4向炎症基因的启动子和增强子募集，以促进RNAPII介导的eRNA和mRNA合成。JQ 1对Brd 4的抑制可使H.幽门螺杆菌诱导的NF-κ B依赖性炎症基因亚群的eRNA和mRNA合成JQ 1对H.幽门螺杆菌诱导的Brd 4和RelA之间的相互作用以及Brd 4和RNAPII向炎性基因的启动子和增强子的募集。最后，我们证明了JQ 1抑制H. pylori感染的小鼠这些研究强调了Brd 4在H中的重要性。提示Brd 4可能是治疗幽门螺杆菌感染的潜在靶点。幽门引发的炎症性疾病和癌症。
H. 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 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 RNAPII-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 RNAPII 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.