Prokineticins: novel mediators of inflammatory and contractile pathways at parturition?

Abstract

The onset of labour is associated with inflammatory cascades in the uteroplacental unit, and these are prematurely activated in preterm labour. Infection can induce an inflammatory response, which results in premature onset of the pro-inflammatory parturient cascades and preterm delivery. We have become interested in two proteins called prokineticins and the role they may play in labour and its premature onset. Prokineticin 1 and 2 bind to two G-protein coupled receptors, called prokineticin receptor 1 and 2. Expression of the prokineticins and their receptors is elevated in the uteroplacental unit during labour and they can induce expression of a host of genes known to be important in initiating the inflammatory and contractile events of labour. Prokineticins have also been shown to directly induce contractility of smooth muscles. Analysing the promoter regions of the prokineticins and their receptors highlights their potential regulation by pathways activated by infectious agents. Hence, we propose that infection can result in premature activation of prokineticin expression and signalling in the uteroplacental unit and this initiates a premature inflammatory and contractile cascade leading to preterm birth. Antagonism of prokineticin action may provide a suitable therapy for preterm labour that targets both inflammation and contractile pathways.

Prokineticin receptor variants (PKR1-I379V and PKR2-V331M) are protective genotypes in human early pregnancy

“…EG-VEGF, PROKR1, and PROKR2 were recently shown to play critical roles in inflammatory and immune responses in human pregnancy (Dorsch et al 2005, Gorowiec et al 2011, Shaw et al 2010. EG-VEGF and its receptors are up-regulated in myometrium and placenta and may act as mediators for initiating term or preterm parturition to regulate a group of genes, mainly chemokines and cytokines, gearing toward a pro-inflammatory response (Catalano et al 2010, Gorowiec et al 2011. In the patients of Chlamydia trachomatis infection, increased tubal expression of PROKR2 via TLR2-mediated NFkB activation was proposed to predispose to tubal implantation (Shaw et al 2010).…”

Role of EG-VEGF in Human Placentation: Physiological and Pathological Implications

“…However, insightful work on EG-VEGF throughout pregnancy came from our group with a focus on early pregnancy and from the group of Dr Jabbour with more focus on the decidual unit, at the term of human gestation (Catalano et al, 2010, Maldonado-Perez et al, 2007.…”

“…The labor onset is known to be associated with inflammatory cascades in the uteroplacental unit, and EG-VEGF has been shown to regulate the production of proinflammatory cytokines and to be involved in the inflammatory response in the placenta (Catalano et al, 2010, Denison et al, 2008, Evans et al, 2008. Therefore, antagonism of prokineticin action may provide a therapy for preterm labor caused by early inflammation and contractile pathways.…”

Prokinéticines

“…Des études complémentaires sont nécessaires pour déterminer si l'augmentation de PROK1 est la cause ou la consé-quence de ces maladies placentaires. Les prokinéticines sont des acteurs potentiels de l'accouchement prématuré et de l'accouchement à terme [30]. L'augmentation des transcrits des deux prokinéticines dans le myomètre pendant le travail, et la présence des prokinéticines et de leurs récepteurs au sein de l'unité utéro-placentaire à terme, suggèrent une action globale des prokinéticines dans le déclenchement du travail [30].…”

“…Les prokinéticines sont des acteurs potentiels de l'accouchement prématuré et de l'accouchement à terme [30]. L'augmentation des transcrits des deux prokinéticines dans le myomètre pendant le travail, et la présence des prokinéticines et de leurs récepteurs au sein de l'unité utéro-placentaire à terme, suggèrent une action globale des prokinéticines dans le déclenchement du travail [30]. Les prokinéticines induisent des cascades pro-inflammatoires et augmentent la contractilité des cellules musculaires lisses du myomètre, deux processus qui participent au déclenchement du travail prématuré et à terme [30].…”