Targeting bromodomain-contaning proteins to prevent spontaneous preterm birth
Targeting bromodomain-contaning proteins to prevent spontaneous preterm birth
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DOI：
10.1042/cs20190919
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发表时间：
2019-12-01
期刊：
影响因子：
6
通讯作者：
Lappas, Martha
中科院分区：
文献类型：
--
作者：
Lim, Ratana;Nguyen-Ngo, Caitlyn;Lappas, Martha
早产是一项全球性的医疗保健挑战。自发性早产（sPTB）通常由炎症引起，但目前尚无有效的治疗方法。含溴结构域和额外末端基序（BET）蛋白，即含溴结构域蛋白（Brd）2（Brd2）、Brd3和Brd4调节非妊娠组织中的炎症。Brd2 - 4在人类妊娠中的作用尚不清楚。本研究利用人类和小鼠模型，确定了Brd蛋白在炎症诱导分娩过程中所起的作用。通过人类临床样本，我们证明分娩和感染会增加子宫和胎膜中Brds的表达。在原代人子宫肌层、羊膜和蜕膜细胞中，我们发现全面抑制Brd蛋白以及选择性抑制Brds，可抑制炎症诱导的参与子宫肌层收缩和胎膜破裂的介质的表达。重要的是，小鼠模型研究表明，泛Brd抑制剂JQ1可减轻细菌内毒素脂多糖（LPS）诱导的宫内炎症，并降低LPS诱导分娩的效力。这些结果表明BET蛋白是减少与自发性早产相关炎症的新型治疗靶点。
Preterm birth is a global healthcare challenge. Spontaneous preterm birth (sPTB) is commonly caused by inflammation, yet there are currently no effective therapies available. The 3 Bromodomain and Extra-Terminal motif (BET) proteins, Bromodomain-containing protein (Brd) 2 (Brd2), Brd3 and Brd4 regulate inflammation in non-gestational tissues. The roles of Brd2-4 in human pregnancy are unknown.Using human and mouse models, the present study has identified the Brd proteins part of the process by which inflammation induces parturition. Using human clinical samples, we demonstrate that labor and infection increase the expression of Brds in the uterus and fetal membranes. In primary human myometrial, amnion and decidual cells, we found that global Brd protein inhibition, as well as selective inhibition of Brds, suppressed inflammation-induced expression of mediators involved in myometrial contractions and rupture of fetal membranes. Importantly, studies in the mouse model demonstrate that the pan-Brd inhibitor JQ1 reduced intrauterine inflammation induced by bacterial endotoxin 2 LPS as well as decreasing the effectiveness of LPS to induce parturition. These results implicate BET proteins as novel therapeutic targets for reducing inflammation associated with spontaneous preterm labor.