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-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.
Highlights
More than 15 million babies are born preterm each year (Blencowe et al 2013), of which around 1 million die from associated complications
We have previously shown that the administration of S. abortus LPS activates toll-like receptor-4 (TLR4)/Jun N-terminal kinase (JNK) signalling in an experimental model of preterm labour (PTL) (Pirianov et al 2009)
In the first series of experiments we determined the ability of co-administration of D-JNK inhibitory peptide (D-JNKI) (0–5 mg) to block S. abortus LPS-induced TLR4/JNK activation in the myometrium and in the fetal brain in this mouse model of PTL
Summary
More than 15 million babies are born preterm each year (Blencowe et al 2013), of which around 1 million die from associated complications. Intrauterine infection and/or inflammation plays an important aetiological role in early preterm delivery and is a risk factor for subsequent CP in both term and preterm infants (Wu & Colford 2000). Inflammation represents a common biochemical pathway critically involved in both term and preterm labour (PTL; Romero et al 2006). To study the underlying biochemistry of inflammation-associated PTL, several investigators have developed mouse models based on intrauterine or systemic injection of bacteria or bacterial lipopolysaccharide (Hirsch et al 1995, Kaga et al 1996, Elovitz et al 2003, Elovitz & Mrinalini 2004). Bacterial products induce PTL through interaction with toll-like receptor-4 (TLR4) and subsequent activation of proinflammatory and pro-contractile pathways within the uterus. Studies using TLR4 mutant mice show that TLR4 plays an essential role in LPS-induced PTL (Elovitz et al 2003, Wang & Hirsch 2003).
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