Franzè Eleonora, Laudisi Federica, Maresca Claudia, Di Grazia Antonio, Iannucci Andrea, Pacifico Teresa, Ortenzi Angela, Sica Giuseppe, Lolli Elisabetta, Stolfi Carmine, Monteleone Ivan, Monteleone Giovanni
Department of Systems Medicine, University of Rome "TOR VERGATA", Rome, Italy.
Department of Biomedicine and Prevention, University of "Tor Vergata", 00133 Rome, Italy.
J Crohns Colitis. 2024 Jul 2. doi: 10.1093/ecco-jcc/jjae104.
Bromodomain-containing protein 4 (BRD4), one of the components of the bromodomain and extraterminal domain (BET) family, is a transcriptional and epigenetic regulator of cellular proliferation and cytokine production. In this study, we assessed whether BRD4 regulates the cytokine response in inflammatory bowel diseases (IBD).
BRD4 expression was analyzed in intestinal mucosal samples of patients with ulcerative colitis (UC), patients with Crohn's disease (CD), normal controls (CTRs), and mice with chemically-induced colitis by real-time PCR, Western blotting, and confocal microscopy. Cytokine production was evaluated in lamina propria mononuclear cells (LPMCs) of IBD patients and mucosal tissues of colitic mice treated with BRD4 inhibitors. Finally, we evaluated the effect of JQ1, an inhibitor of the BRD4 signaling pathway, on the course of murine colitis.
BRD4 RNA and protein expression was up-regulated in the inflamed mucosa of patients with UC and patients with CD as compared to the uninvolved areas of the same patients and CTRs, and in the inflamed colon of colitic mice. Knockdown of BRD4 with a specific antisense oligonucleotide in IBD LPMCs led to reduced expression of TNF-α, IL-6, IFN-γ, and IL-17A. Administration of JQ1 to colitic mice inhibited the inflammatory cytokine response and attenuated the ongoing colitis.
This is the first study showing the up-regulation of BRD4 in IBD and suggesting the role of such a protein in the positive control of the inflammatory cytokine response in the gut.
含溴结构域蛋白4（BRD4）是溴结构域与额外末端结构域（BET）家族的成员之一，是细胞增殖和细胞因子产生的转录及表观遗传调节因子。在本研究中，我们评估了BRD4是否调节炎症性肠病（IBD）中的细胞因子反应。
通过实时聚合酶链反应、蛋白质免疫印迹法和共聚焦显微镜，分析溃疡性结肠炎（UC）患者、克罗恩病（CD）患者、正常对照（CTR）以及化学诱导性结肠炎小鼠的肠黏膜样本中BRD4的表达。评估BRD4抑制剂处理的IBD患者固有层单核细胞（LPMC）和结肠炎小鼠黏膜组织中的细胞因子产生情况。最后，我们评估了BRD4信号通路抑制剂JQ1对小鼠结肠炎病程的影响。
与同一患者的非病变区域和CTR相比，UC患者和CD患者炎症黏膜中以及结肠炎小鼠炎症结肠中的BRD4 RNA和蛋白表达上调。用特异性反义寡核苷酸敲低IBD LPMC中的BRD4导致肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、干扰素-γ（IFN-γ）和白细胞介素-17A（IL-17A）的表达降低。给结肠炎小鼠施用JQ1可抑制炎性细胞因子反应并减轻正在进行的结肠炎。
这是第一项显示IBD中BRD4上调并提示该蛋白在肠道炎性细胞因子反应阳性调控中作用的研究。
