Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality

Pirianov, Grisha and MacIntyre, David A and Lee, Yun and Waddington, Simon N and Terzidou, Vasso and Mehmet, Huseyin and Bennett, Phillip R (2015) Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality. Reproduction, 150 (4). pp. 269-277. ISSN 1470-1626

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Official URL: https://doi.org/10.1530/REP-15-0258

Abstract

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-kB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-kB, showed that selective inhibition of NF-kB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-kB, 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.

Item Type: Journal Article
Faculty: Faculty of Science & Technology
Depositing User: Ian Walker
Date Deposited: 09 Mar 2018 12:37
Last Modified: 09 Mar 2018 12:37
URI: http://arro.anglia.ac.uk/id/eprint/702818

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