2Imperial College Parturition Research Group, Institute of Reproduction and Developmental Biology, Imperial College London, Hammersmith Campus, London, W12 0NN, UK.
FASEB J. 2014 May;28(5):2358-68. doi: 10.1096/fj.13-247783. Epub 2014 Feb 4.
Activation of uterine inflammatory pathways leads to preterm labor (PTL), associated with high rates of neonatal mortality and morbidity. The transcription factors nuclear factor κB (NFκB) and activator protein 1 (AP-1) regulate key proinflammatory and procontractile genes involved in normal labor and PTL. Here we show that NFκB activation normally occurs in the mouse myometrium at gestation day E18, prior to labor, whereas AP-1 and JNK activation occurs at labor onset. Where labor was induced using the progesterone receptor antagonist RU486, NFkB and AP-1/JNK activation both occurred at the time of labor (20 h compared to 60 h in DMSO-treated controls). Using an LPS (Escherichia coli: serotype O111)-induced PTL model that selectively activates AP-1 but not NFkB, we show that myometrial AP-1 activation drives production of cytokines (Il-6, Il-8, and Il-1β), metalloproteinases (Mmp3 and Mmp10), and procontractile proteins (Cox-2 and Cx43) resulting in PTL after 7 h. Protein levels of CX43 and IL-1β, and IL-1β cleavage, were increased following LPS-induced activation of AP-1. Inhibition of JNK by SP600125 (30 mg/kg) delayed PTL by 6 h (7.5 vs. 13.5 h P<0.05). Our data reveal that NFκB activation is not a functional requirement for infection/inflammation-induced preterm labor and that AP-1 activation is sufficient to drive inflammatory pathways that cause PTL.
子宫炎症途径的激活导致早产（PTL），与新生儿死亡率和发病率高有关。转录因子核因子 κB（NFκB）和激活蛋白 1（AP-1）调节正常分娩和 PTL 中涉及的关键促炎和促收缩基因。在这里，我们表明 NFkB 激活通常发生在妊娠第 18 天的小鼠子宫肌层，在分娩之前，而 AP-1 和 JNK 激活发生在分娩开始时。在使用孕激素受体拮抗剂 RU486 诱导分娩的情况下，NFkB 和 AP-1/JNK 激活都发生在分娩时（与 DMSO 处理对照相比，20 小时与 60 小时）。使用 LPS（大肠杆菌：血清型 O111）诱导的 PTL 模型，该模型选择性激活 AP-1 但不激活 NFkB，我们表明，子宫肌层的 AP-1 激活导致细胞因子（IL-6、IL-8 和 IL-1β）、金属蛋白酶（Mmp3 和 Mmp10）和促收缩蛋白（Cox-2 和 Cx43）的产生，导致 PTL 在 7 小时后发生。在 LPS 诱导的 AP-1 激活后，CX43 和 IL-1β 的蛋白水平以及 IL-1β 的切割增加。用 SP600125（30mg/kg）抑制 JNK 可将 PTL 延迟 6 小时（7.5 与 13.5 小时，P<0.05）。我们的数据表明，NFkB 激活不是感染/炎症诱导的早产的功能要求，而 AP-1 激活足以驱动导致 PTL 的炎症途径。
