Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality.
Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality.
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DOI：
10.1530/rep-15-0258
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Bennett PR
中科院分区：
文献类型：
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作者：
Pirianov G;MacIntyre DA;Lee Y;Waddington SN;Terzidou V;Mehmet H;Bennett PR
早产（PTL）通常与感染和/或炎症有关。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）/AP 1或NF-κ B驱动的导致PTL的炎症通路。先前使用激活JNK/AP-1和NF-κB的流产沙门氏菌LPS的研究表明，选择性抑制NF-κB可延迟分娩并改善幼崽结局。当使用上调JNK/AP-1但不上调NF-κB的大肠杆菌LPS（O 111）诱导分娩时，抑制JNK/AP-1活化也延迟分娩。在这项研究中，为了确定JNK作为PTL治疗靶点的潜在作用，我们研究了JNK信号转导对S.小鼠中LPS诱导的PTL。宫内注射S.妊娠小鼠流产LPS导致母体子宫和胎儿脑中JNK的激活，促炎蛋白考克斯-2、CXCL 1和CCL 2的上调，子宫肌层中cPLA 2的磷酸化，以及PTL的诱导。特异性JNK抑制肽（D-JNKI）的联合给药特异性抑制JNK延迟LPS诱导的早产和降低胎儿死亡率。这与子宫肌层cPLA 2磷酸化和促炎蛋白合成的抑制有关。此外，我们报告说，D-JNKI抑制JNK/JNK 3和caspase-3的激活，这是在新生儿脑神经细胞死亡的重要介质。我们的数据表明，TLR 4激活的JNK信号通路的特异性抑制具有作为感染/炎症相关PTL的管理和预防对新生儿大脑的相关有害影响的治疗方法的潜力。
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.