Gao Lu, Wang Gang, Liu Wei-Na, Kinser Holly, Franco Hector L, Mendelson Carole R
Department of Physiology (L.G., G.W., W.L.), Second Military Medical University, Shanghai 200433, People's Republic of China; Department of Biochemistry (L.G., H.K., C.R.M.) and Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Obstetrics and Gynecology (C.R.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
J Clin Endocrinol Metab. 2016 Oct;101(10):3646-3656. doi: 10.1210/jc.2016-2078. Epub 2016 Jul 26.
The initiation of term and preterm labor is associated with an up-regulated inflammatory response in myometrium; however, the underlying signaling pathways remain incompletely defined.
To define the regulatory mechanisms that mediate the increased myometrial inflammatory response leading to labor, we investigated the roles of microRNAs (miRNA/miR).
Human myometrial tissues, isolated smooth muscle cells, and animal models were used to study miR-181a regulation of uterine inflammatory pathways and contractility.
Myometrial tissues from 15 term pregnant women undergoing elective cesarean section (not in labor) and 10 term pregnant women undergoing emergency cesarean section (in labor) were used.
Expression of the highly conserved microRNA, miR-181a, was significantly decreased in mouse and human myometrium during late gestation. By contrast, the putative miR-181a targets, TNF-α, and estrogen receptor (ER)-α, and the validated target, c-Fos, key factors in the inflammatory response leading to parturition, were coordinately up-regulated. In studies using human myometrial cells, overexpression of miR-181a mimics repressed basal as well as IL-1β-induced TNF-α, C-C motif chemokine ligand 2 and 8 expression, whereas the expression of the antiinflammatory cytokine, IL-10, was increased. Overexpression of miR-181a dramatically inhibited both spontaneous and IL-1β-induced contraction of human myometrial cells. Notably, miR-181a directly targeted ERα and decreased its expression, whereas estradiol-17β reciprocally inhibited expression of mature miR-181a in myometrial cells.
Thus, increased estradiol-17β/ERα signaling in myometrium near term inhibits miR-181a, resulting in a further increase in ERα and proinflammatory signaling. This escalating feedback loop provides novel targets and therapeutic strategies for the prevention of preterm labor and its consequences.
足月分娩和早产的启动与子宫肌层中上调的炎症反应相关；然而，潜在的信号通路仍未完全明确。
为了确定介导子宫肌层炎症反应增加导致分娩的调节机制，我们研究了微小RNA（miRNA/miR）的作用。
使用人子宫肌层组织、分离的平滑肌细胞和动物模型来研究miR-181a对子宫炎症途径和收缩性的调节作用。
使用了15名接受择期剖宫产（未临产）的足月孕妇和10名接受急诊剖宫产（临产）的足月孕妇的子宫肌层组织。
在妊娠晚期，高度保守的微小RNA miR-181a在小鼠和人子宫肌层中的表达显著降低。相比之下，miR-181a的假定靶标肿瘤坏死因子-α（TNF-α）和雌激素受体（ER）-α，以及已验证的靶标原癌基因c-Fos（导致分娩的炎症反应中的关键因子）则协同上调。在使用人子宫肌层细胞的研究中，miR-181a模拟物的过表达抑制了基础以及白细胞介素-1β（IL-1β）诱导的TNF-α、C-C基序趋化因子配体2和8的表达，而抗炎细胞因子IL-10的表达增加。miR-181a的过表达显著抑制了人子宫肌层细胞的自发收缩和IL-1β诱导的收缩。值得注意的是，miR-181a直接靶向ERα并降低其表达，而雌二醇-17β则相互抑制子宫肌层细胞中成熟miR-181a的表达。
因此，妊娠末期子宫肌层中雌二醇-17β/ERα信号的增加抑制了miR-181a，导致ERα和促炎信号进一步增加。这种不断升级的反馈环为预防早产及其后果提供了新的靶点和治疗策略。
