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首页> 外文期刊>Reviews of Reproduction >Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality
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Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality

机译：对c-Jun N端激酶的特异性抑制可延迟早产并降低死亡率

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Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-κB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-κB, showed that selective inhibition of NF-κB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-κB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain.
机译：早产（PTL）通常与感染和/或炎症相关。来自不同细菌的脂多糖（LPS）可用于独立或相互激活Jun N末端激酶（JNK）/ AP1-或NF-κB驱动的导致PTL的炎症途径。先前使用流产沙门氏菌LPS激活JNK / AP-1和NF-κB的研究表明，选择性抑制NF-κB会延迟分娩并改善幼仔结局。在使用上调JNK / AP-1但不上调NF-κB的大肠杆菌LPS（O111）诱导分娩的情况下，抑制JNK / AP-1的活化也会延迟劳动。在这项研究中，为了确定JNK作为PTL治疗靶标的潜在作用，我们研究了JNK信号传导对小鼠A. Abortus LPS诱导的PTL的特定作用。对怀孕小鼠进行宫内注射S. Abortus LPS会导致母体子宫和胎儿脑中的JNK活化，促炎蛋白COX-2，CXCL1和CCL2上调，子宫内膜中cPLA2的磷酸化以及PTL的诱导。通过共同施用特定的D-JNK抑制肽（D-JNKI）来特异性抑制JNK可以延迟LPS诱导的早产并降低胎儿死亡率。这与抑制子宫肌层cPLA2磷酸化和促炎蛋白合成有关。此外，我们报道D-JNKI抑制JNK / JNK3和caspase-3的激活，这是新生儿脑神经细胞死亡的重要介体。我们的数据表明，特异性抑制TLR4激活的JNK信号通路具有潜在的治疗感染/炎症相关PTL和预防对新生儿脑部有害作用的治疗方法。

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