Prokineticin 1 Induces Inflammatory Response in Human Myometrium

Gorowiec, Marta R.; Catalano, Rob D.; Norman, Jane E.; Denison, Fiona C.; Jabbour, Henry N.

doi:10.1016/j.ajpath.2011.08.029

Cited by 22 publications

(14 citation statements)

References 46 publications

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“…PROK1 mRNA expression is increased in human placenta and myometrium at term, and ex vivo treatment of these tissues with PROK1 induces a pro-inflammatory response (Denison et al . 2008, Gorowiec et al . 2011).…”

Section: Discussionmentioning

confidence: 99%

“…This hypothesis may be supported by our finding that Prok1 expression peaks on D18, and not on D19 like the other pro-inflammatory mediators analysed, suggesting that in the mouse, transient endogenous expression occurs rather than a prolonged amplification of pro-inflammatory mediator expression driven by PROK1 as hypothesised to occur in humans (Catalano et al . 2010, Gorowiec et al . 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, 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).…”

Section: Introductionmentioning

confidence: 99%

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Prokineticin 1 induces a pro-inflammatory response in murine fetal membranes but does not induce preterm delivery

Lannagan¹,

Wilson²,

Denison³

et al. 2013

Reproduction

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Prokineticin 1 induces a pro-inflammatory response in murine fetal membranes but does not induce preterm delivery

Lannagan¹,

Wilson²,

Denison³

et al. 2013

Reproduction

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“…Here, at least two independent population bottleneck or founder events, both having an impact on sequence variants of the same gene (PROKR2), would be required to explain on their own (i.e., without an additional positive selection pressure, see below) the two different PROKR2 mutations most prevalent in the Maghrebian patients (p.P290S, p.R85C), which may be considered rather unlikely. Another possible explanation is balancing selection (22), whereby some positive selection pressure would exert on the PROKR2 loss-of-function mutations in the heterozygous state, for instance because of the suspected involvement of prokineticin-signaling in preterm labor and premature birth (23,24), or because this prokineticin receptor might also be a cell surface receptor to specific infectious agents, as shown for another G protein-coupled receptor, the CC chemokine receptor-5, and human immunodeficiency virus type 1 infection (25,26). In most reported examples of balancing selection, however, the frequency of individuals heterozygous for the advantageous mutations is higher than the frequency of PROKR2 heterozygotes we observed in the Maghrebian population, i.e.…”

Section: Discussionmentioning

confidence: 99%

Greater prevalence of PROKR2 mutations in Kallmann syndrome patients from the Maghreb than in European patients

Sarfati

Fouveaut

Leroy

et al. 2013

European Journal of Endocrinology

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Context: Kallmann syndrome (KS) is a genetically heterogeneous developmental disorder that associates hypogonadotropic hypogonadism and anosmia. Various causative genes have been identified, but their respective involvement in different world regions is poorly documented. Objective: We aimed to compare the prevalence of mutations in five routinely analyzed KS genes between Maghrebian and European patients. Methods: Blood samples from 120 presumably unrelated Maghrebian patients were collected for DNA sequencing by the Sanger technique. The prevalence of the non-synonymous mutations in KAL1, FGFR1, FGF8, PROKR2, and PROK2 was determined for each gene, and compared with those previously obtained from the analysis of 712 European patients. Results: Diverse mutations in PROKR2, a gene involved both in monogenic recessive and digenic/oligogenic KS transmission modes, were found in 23.3% of the Maghrebian patients, but only in 5.1% of the European patients (Fisher's exact test, P!0.001), whereas mutations in each of the other four KS genes were present either at similar frequencies in the Maghrebian and European patients (KAL1, PROK2, FGF8, from 6.6 to 0.8%; Fisher's exact test, PO0.4 for all comparisons) or at a lower frequency in Maghrebian patients (FGFR1, 5.0 vs 11.7%; Fisher's exact test, P!0.05). Homozygosity resulting from consanguineous marriages was not sufficient to account for the greater prevalence of PROKR2 mutations in the Maghrebian patients. Conclusions: The great prevalence of PROKR2 mutations in Maghrebian patients has practical consequences for molecular diagnosis of the disease and genetic counseling in the Maghrebian population.

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“…Besides this prostaglandins are involved in cervical ripening and uterine contractions and thereby elevated COX-2 is an important marker of ongoing labour. Based on this and microarray analysis revealing expression of PROK2 increasing with the onset of labour in both the myometrium and cervix [49], it was proposed by Gorwiec et al (2011) that PROK1 and PROKR1 may constitute an initiatory pathway for an inflammatory response in third trimester placenta [50]. PROK'S have also been shown to directly induce contractility of smooth muscles.…”

Section: Prok In Third Trimester-human Placenta-inflammatory Mediatormentioning

confidence: 98%

An update on the role of prokineticins in human reproduction-potential therapeutic implications

Kaur¹,

Allahbadia²,

Singh³

2013

OJGen

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Objective: Prokineticin-1 (PROK1) is a recently described protein with a wide range of functions including tissue specific angiogenesis, modulation of inflammatory responses and regulation of haematopoiesis. PROK1 has been found in the steroidogenic organs like ovary, testis, adrenal and specially placenta and they have been found to have a role in development of the olfactory system and GnRH system. The aim was to update the role of PROK1 and PROK2 in human reproduction since the review was provided by Maldono-Perez (2007) on the potentials of prokineticins in reproduction. Design: A review of international scientific literature by a search of Pubmed and the authors files was done for citation of articles relevant to prokineticins in reproduction, be it its role in ovary, testis, uterus with special emphasis on implantation, normal pregnancy, in labour, pathophysiological states like tubal pregnancy, pcos, various genital tumours, and cases of isolated hypogonadotropic hypogonadism with mutations with PROK2/ PROKR2 and studies detailing functional mechanisms. Results: In the normal cycle, PROK1 has been found to have important roles in implantation, regulating several genes like COX-2, IL-8, IL-11, CTGF related to implantation. Initially murine studies revealed a critical role of PROK2 pathway on olfactory bulb morphogenesis and GnRH secretion which was accidentally discovered and since then several studies on mutations in PROK2/PROKR2 showed that they underlie some case of KS in humans. Although in mouse heterozygote state is not associated with clinical phenotype, most of human mutations are heterozygous. Conclusions: Role of PROK-1 in the process of implantation, with a deeper understanding of the process success rates in IVF and ART can be improved, besides understanding the pathophysiology of tubal pregnancy. Further presence in ovarian follicles of PROK1 can be used to plan a strategy for treating pcos. Development of antagonism of PROK'S may be a helpful strategy in treating preterm labour.

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Prokineticin 1 Induces Inflammatory Response in Human Myometrium

Cited by 22 publications

References 46 publications

Prokineticin 1 induces a pro-inflammatory response in murine fetal membranes but does not induce preterm delivery

Prokineticin 1 induces a pro-inflammatory response in murine fetal membranes but does not induce preterm delivery

Greater prevalence of PROKR2 mutations in Kallmann syndrome patients from the Maghreb than in European patients

An update on the role of prokineticins in human reproduction-potential therapeutic implications

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