Abstract
The mechanisms that regulate the induction of term or preterm delivery (PTD) are not fully understood. Infection is known to play a role in the induction of pro-inflammatory cascades in uteroplacental tissues associated with preterm pathological parturition. Similar but not identical cascades are evident in term labour. In the current study, we used a mouse model to evaluate the role of prokineticins in term and preterm parturition. Prokineticins are multi-functioning secreted proteins that signal through G-protein-coupled receptors to induce gene expression, including genes important in inflammatory responses. Expression of prokineticins (Prok1 and Prok2) was quantified in murine uteroplacental tissues by QPCR in the days preceding labour (days 16–19). Prok1 mRNA expression increased significantly on D18 in fetal membranes (compared with D16) but not in uterus or placenta. Intrauterine injection of PROK1 on D17 induced fetal membrane mRNA expression of the pro-inflammatory mediators Il6, Il1b, Tnf, Cxcl2 and Cxcl5, which are not normally up-regulated until D19 of pregnancy. However, intrauterine injection of PROK1 did not result in PTD. As expected, injection of lipopolysaccharide (LPS) induced PTD, but this was not associated with changes in expression of Prok1 or its receptor (Prokr1) in fetal membranes. These results suggest that although Prok1 exhibits dynamic mRNA regulation in fetal membranes preceding labour and induces a pro-inflammatory response when injected into the uterus on D17, it is insufficient to induce PTD. Additionally, prokineticin up-regulation appears not to be part of the LPS-induced inflammatory response in mouse fetal membranes.
Highlights
The factors that trigger the onset of parturition at term in humans (w39 weeks) are not yet fully understood, inflammation in uteroplacental tissues and increased priming of leukocyte activation in maternal peripheral blood are well documented (Peltier 2003, Haddad et al 2006, Bollapragada et al 2009, Challis et al 2009, Yuan et al 2009)
We investigated the pro-inflammatory response of fetal membranes to LPS and prokineticin 1 (PROK1) in vivo using a model of infection-induced Preterm delivery (PTD)
We subsequently investigated the temporal expression of Ptgs2, Il6, Il1b, Tnf, Cxcl2 and Cxcl5 between D16 and 19 of pregnancy and all were shown to significantly increase on D19 in fetal membranes (Supplementary Figure 3, see section on supplementary data given at the end of this article)
Summary
The factors that trigger the onset of parturition at term in humans (w39 weeks) are not yet fully understood, inflammation in uteroplacental tissues and increased priming of leukocyte activation in maternal peripheral blood are well documented (Peltier 2003, Haddad et al 2006, Bollapragada et al 2009, Challis et al 2009, Yuan et al 2009). 582 T R M Lannagan and others regulator of pro-inflammatory mediators (Akira et al 2006, Doyle & O’Neill 2006), resulting in the premature expression of cytokines and chemokines in gestational tissues This process culminates in early onset of cervical ripening, uterine contractions and PTD. We have recently demonstrated that prokineticins are up-regulated at term in uteroplacental tissues and that ex vivo treatment with PROK1 induces a cascade of pro-inflammatory pathways in human placenta and myometrial tissue collected from pregnant women at term (Denison et al 2008, Gorowiec et al 2011) These data taken together demonstrate the potential role for prokineticins in regulating inflammatory pathways associated with term parturition and their possible involvement in preterm labour. This study was designed to characterise the expression of prokineticins in mouse uteroplacental tissues in the Reproduction (2013) 146 581–591 days preceding labour and to investigate the role of prokineticins in term and preterm parturition using a mouse model of infection-induced PTD
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