Inflammatory processes in preterm and term parturition

Perinatal Research Centre, Departments of Obstetrics and Gynecology, Pediatrics, Physiology, and Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.
Journal of Reproductive Immunology (Impact Factor: 2.82). 07/2008; 79(1):50-7. DOI: 10.1016/j.jri.2008.04.002
Source: PubMed

ABSTRACT A role for the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor alpha (TNF-alpha) is evident in term and preterm delivery, and this is independent of the presence of infection. All uterine tissues progress through a staged transformation near the end of pregnancy that leads from relative uterine quiescence and maintenance of pregnancy to the activation of the uterus that prepares it for the work of labour and production of stimulatory molecules that trigger the onset of labour and delivery. The uterus is activated by pro-inflammatory cytokines through stimulation of the expression and production of uterine activation proteins (UAPs). One of these actions is the stimulation of prostaglandin (PG) synthesis. Particularly important for labour is PGF(2alpha) and its receptor, PTGFR. In addition, pro-inflammatory cytokines are able to increase the synthesis of matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and the progesterone receptor C isoform, which leads to decreased tissue progesterone responsiveness. Some of these effects are replicated by PGF(2alpha), suggesting that it may act via its receptor to amplify the direct actions of cytokines. In turn, VEGF may enhance leukocyte recruitment to the uterus, and MMP-9 may promote activation of inactive pro-form cytokines. Pro-inflammatory cytokines also decrease the activity of 11beta-hydroxysteroid dehydrogenase, which likely increases intrauterine cortisol concentrations. In turn, cortisol may drive PG synthesis. Together these feed-forward mechanisms activate the uterus, trigger the production of uterine contractile stimulants and lead to labour and delivery.

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    • "inflammatory process with pro-inflammatory cytokines like IL-8 and TNF-a playing a role [Christiaens et al. 2008; Elliott 2001; Norman et al. 2007]. Thus, a balance between the pro and anti-inflammatory modulators at the feto-maternal interface is crucial for maintenance of pregnancy. "
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    ABSTRACT: Abstract Peroxisome proliferator-activated receptor-gamma (PPAR-γ) belongs to the nuclear hormone receptor superfamily. Apart from being involved in lipid metabolism, like its other subtypes PPAR α and β, it is implicated to be crucial for successful placentation. While its role in extravillous trophoblast (EVT) differentiation has been studied, the involvement in villous trophoblast (VT) differentiation, fatty-acid metabolism, inflammatory responses, and oxidative pathways during pregnancy deserves more attention. PPAR-γ's potential role in balancing structural development and functional responsibilities at the maternal-fetal interface suggest a more central role for the receptor. The central role of PPAR-γ in pathways related to placental pathologies suggests a potential role of PPAR-γ in placental function. The molecular regulation of PPAR-γ in this context has been widely disregarded. In this review, we discuss the less explored functions of PPAR-γ in the areas of immunological responses and management of oxidative stress in the placenta. We also shed light on the involvement of PPAR-γ in pathologic pregnancies and briefly discuss the current models in the field. The ability to modulate PPAR-γ's activity using already available drugs makes it a tempting therapeutic target. Elucidation of the molecular pathways and specific targets regulated by PPAR-γ will provide more information on the role of PPAR-γ in placentation and related disorders in pregnancy. Furthermore it will close the critical gap in our knowledge about the differential regulation of PPAR-γ in the two trophoblast lineages. This will help to evaluate the usefulness and timing of PPAR-γ modulation in at risk pregnancies to improve placental and endothelial function.
    Systems Biology in Reproductive Medicine 12/2014; 61(2):1-7. DOI:10.3109/19396368.2014.991881 · 1.60 Impact Factor
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    • "Consistent with this, infection and/or inflammation are the only well-defined pathological processes at the molecular level in which a firm causal link with preterm labour has been established . Although between 25 and 40% of preterm births are thought to be attributed to intrauterine microbial infection (Goldenberg et al. 2000), inflammation in the absence of infection can be sufficient to cause preterm labour (Shim et al. 2004, Christiaens et al. 2008). "
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    ABSTRACT: Preterm birth occurs in 10-12% of pregnancies and is the primary cause of neonatal mortality and morbidity. Tocolytic therapies have long been the focus for the prevention of preterm labour yet they do not significantly improve neonatal outcome. A direct causal link exists between infection-induced inflammation and preterm labour. Tocolytics may therefore cause more harm by keeping the fetus in a hostile environment. Since inflammation and infection are independent risk factors for poor neonatal outcome, recent research focus has shifted towards exploring the potential for anti-inflammatory strategies. NF-κB is a transcription factor that controls the expression of many labour associated genes including COX-2, prostaglandins and the oxytocin receptor as well as key inflammatory genes. Targeting the inhibition of NF-κB is therefore an attractive therapeutic approach for both the prevention of preterm labour and for reducing neonatal exposure to inflammation. Whilst prostaglandins are considered to be pro-labour and pro-inflammatory, the cyclopentenone prostaglandin 15-deoxy-Δ12,14PGJ2 (15dPGJ2) exhibits anti-inflammatory properties via the inhibition of NF-κB in human amniocytes, myocytes and peripheral blood mononuclear cells in vitro. 15dPGJ2 also delays inflammation induced preterm labour in the mouse and significantly increases pup survival. This review examines the current understanding of inflammation in the context of labour and discusses how anti-inflammatory prostaglandins may hold promise for the prevention of preterm labour and improved neonatal outcome.
    Reproduction (Cambridge, England) 06/2014; 148(2). DOI:10.1530/REP-13-0587 · 3.17 Impact Factor
    • "During pregnancy, cytokines act in concert at the materno-placental interface balancing immunological tolerance. Indeed, both antiand pro-inflammatory cytokines participate in several important events such as trophoblastic invasion, hormonal production and delivery process [15] [16] [17] [18] [19]. However, exacerbated production of pro-inflammatory cytokines as well as vitamin D deficiency are associated with miscarriage, preterm labor and preeclampsia [20] [21]. "
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    ABSTRACT: Placenta is an important source of endocrine and immunological factors. During pregnancy, calcitriol, the active metabolite of vitamin D, is also metabolized by decidua and placental tissue by means of CYP27B1 and CYP24A1 for synthesis and inactivation of calcitriol respectively. Calcitriol production is regulated by several factors in a tissue-specific manner. However, the association of pro-inflammatory cytokines on calcitriol metabolism has not been studied in human placenta. The aim of the present study was to investigate the effects of TNF-α, INF-γ, IL-6 and IL-1β upon CYP27B1 and CYP24A1 gene expression in primary cultures of human placental cells. Placentas were obtained immediately after delivery by cesarean section from normotensive women. Cytokine effects upon mRNA of CYPs in enriched trophoblastic cell preparations were evaluated by using qPCR. The results showed that incubation of trophoblasts in the presence of each cytokine resulted in a significant increase of both CYPs expression. Interestingly, TNF-α increased significantly the ratio of CYP24A1/CYP27B1 gene expression, while IFN-γ preferentially induced CYP27B1, whereas IL-1β and IL-6 stimulated gene expression of both CYPs in the same proportion. The results suggest that cytokines among other factors regulate calcitriol metabolism in human placenta; specifically, INF-γ may contribute to calcitriol production while TNF-α favors its catabolism.
    The Journal of steroid biochemistry and molecular biology 12/2013; 144. DOI:10.1016/j.jsbmb.2013.12.007 · 3.63 Impact Factor
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