Evidence for participation of uterine natural killer cells in the mechanisms responsible for spontaneous preterm labor and delivery. Am J Obstet Gynecol 3:1-9

Department of Pediatrics, Women and Infants Hospital of Rhode Island-Warren Alpert Medical School of Brown University, Providence, RI, USA.
American journal of obstetrics and gynecology (Impact Factor: 4.7). 03/2009; 200(3):308.e1-9. DOI: 10.1016/j.ajog.2008.10.043
Source: PubMed


The purpose of this study was to determine in a mouse model whether uterine natural killer (uNK) cell cytotoxic activation induces infection/inflammation-associated preterm labor and delivery.
Wild type or interleukin (IL)-10(-/-) mice were injected intraperitoneally with lipopolysaccharide on gestational day 14. Mice were either killed for collection of uteroplacental tissue, spleen, and serum or allowed to deliver. Uteroplacental tissue was used for histology and characterization of uNK cells.
Low-dose lipopolysaccharide treatment triggered preterm labor and delivery in IL-10(-/-), but not wild type mice, in a manner independent of progesterone levels. Preterm labor and delivery in IL-10(-/-) mice was associated with an increased number and placental infiltration of cytotoxic uNK cells and placental cell death. Depletion of NK cells or tumor necrosis factor (TNF)-alpha neutralization in these mice restored term delivery. Furthermore, TNF-alpha neutralization prevented uNK cell infiltration and placental cell apoptosis.
The uNK cell-TNF-alpha-IL-10 axis plays an important role in the genesis of infection/inflammation-induced preterm labor/delivery.

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    • "Our own in vitro studies have shown that LPS directly induces contractions of isolated human myometrial cells (Hutchinson et al., 2013). Influx of immune cells likely also contributes to the process, although further work is required to define their precise roles (Timmons and Mahendroo, 2006; Murphy et al., 2009; Thaxton et al., 2009; Gonzalez et al., 2011; Rinaldi et al., 2014). Given the link between inflammation and spontaneous labour onset, and the association between intrauterine infection and PTL, there has been a growing interest in examining whether anti-inflammatory agents could be effective novel therapeutic options for PTL (Rinaldi et al., 2011). "
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    ABSTRACT: Preterm birth remains the leading cause of neonatal mortality and morbidity worldwide. There are currently few effective therapies and therefore an urgent need for novel treatments. Although there is much focus on trying to alter gestation of delivery, the primary aim of preterm birth prevention therapies should be to reduce prematurity related mortality and morbidity. Given the link between intrauterine infection and inflammation and preterm labour (PTL), we hypothesised that administration of lipoxins, key anti-inflammatory and pro-resolution mediators, could be a useful novel treatment for PTL. Using a mouse model of infection-induced PTL we investigated whether 15-epi-lipoxin A4 could delay lipopolysaccharide (LPS)-induced PTL and reduce pup mortality. On D17 of gestation mice (n=9-12) were pre-treated with vehicle or 15-epi-lipoxin A4 prior to intrauterine administration of LPS or PBS. Although pre-treatment with 15-epi-lipoxin A4 did not delay LPS-induced PTL, there was a significant reduction in the mortality amongst prematurely delivered pups (defined as delivery within 36 hours of surgery) in mice treated with 15-epi-lipoxin A4 prior to LPS treatment, compared to those receiving LPS alone (p<0.05). Quantitative real time (QRT)-PCR analysis of utero-placental tissues harvested 6 hours post-treatment demonstrated that 15-epi-lipoxin A4 treatment increased Ptgs2 expression in the uterus, placenta and fetal membranes (p<0.05) and decreased 15-Hpgd expression (p<0.05) in the placenta and uterus, suggesting that 15-epi-lipoxin A4 may regulate the local production and activity of prostaglandins. These data suggest that augmenting lipoxin levels could be a useful novel therapeutic option in the treatment of PTL, protecting the fetus from the adverse effects of infection-induced preterm birth. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
    Full-text · Article · Jan 2015 · Molecular Human Reproduction
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    • "Previous studies suggested that cytokine IL-10 might be a determinant for pregnancy success. LPS caused adverse pregnancy outcomes including increased embryo resorption and preterm birth in IL-10-/- mice compared with their wild-type (WT) counterparts even at very low doses [6], [7], [8], and low doses of CpG displayed similar effects [4], [5]. Notably, NOD mice are known to be lower in both regulatory T cells (Treg cell) number [9] and IL-10+ cell number [10], and prone to pregnancy loss even without inflammatory challenge [5], [9]. "
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    ABSTRACT: To elucidate the mechanism by which embryo-resorption and preterm birth were enhanced by pathogenic CpG motif and to develop a counter strategy for normal pregnancy outcome. This is an animal model-based study. In pregnant nonobese diabetic (NOD) mice and wild-type (WT) mice in the same strain background, an infection was mimicked by toll-like receptor 9 (TLR9) activation through CpG1826-injection. In vivo inactivation of IL-10 was performed to enhance pregnancy loss. Regulatory T cells induced by FTY720 in vitro from splenic CD4+CD25-Foxp3- cells (iTreg cells) were transferred to improve pregnancy outcomes in NOD mice. Embryo-resorption and preterm birth were readily induced by CpG1826 in NOD mice, but not in WT mice. However, inactivation of IL-10 using neutralizing antibody injections enhanced pregnancy loss in WT mice exposed to CpG, while adoptive transfer of iTreg cells increased decidual Foxp3+ Treg cells and IL-10+ cell number and rescued pregnancy. NOD mice are prone to abortion and preterm birth. This can be attributed to lacking Treg cells and insufficient IL-10 expression. Adoptive transfer of iTreg cells can rescue CpG-mediated pregnancy failure.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "Experiments using abortive CBA/J female mice mated with DBA/2J male mice show that uNK cells contribute indirectly to miscarriage by producing the proinflammatory cytokines IFN-γ and TNFα that seem to activate a Th1 type response in dendritic cells [84] [85] [86]. Similar to cNK cells, uNK cells also express Toll-like receptors (TLR) 1, 2, 3, 4, 6, 7 and 9 which are reactive to pathogen antigens and trigger pro-inflammatory cytokine releasing by uNK cells [87]; this explains mouse miscarriages that have been induced experimentally by bacterial wall lipopolysaccharides (LPS) and poly(I:C) [88] [89] [90]. The TNFα, TGF-β1, and IFNγ that are produced by uNK cells are associated with control of trophoblast invasion in humans, and an imbalance of these cytokines significantly influences pregnancy, as their inoculation increases the abortion rate in the mice [91] [92]. "
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    ABSTRACT: Uterine-natural killer (uNK) cells are a transient and dominant leukocyte in the uterine mucosa playing a key modulatory role at the maternal-fetal interface to support successful pregnancy. Despite having common bone marrow precursors and phenotypic similarities to circulating blood (c) NK cells found in the lymphoid organs and other mucosa, research has established that uNK cells in the uterine mucosa are a pregnancy-specific subset of NK cells. The ontogeny and phenotype of uNK cells inevitably raises the question of what role an innate immune effector cell containing a full set of cytolytic mediators plays in pregnancy. Extensive contributions from several laboratories have confirmed that human and mice uNK cells produce cytokines and growth factors for adequate uterine angiogenesis and vascular remodeling, control of placental growth, and maintenance of the decidual reaction to benefit the pregnancy. Undoubtedly, uNK cells are critical but not essential for successful pregnancy. Conversely, the expected cytotoxic activity of uNK cell seems to be suppressed in normal pregnancy, yet experimental approaches in mice points to the ability of these cells to have their inherent cytotoxic innate immune response triggered. Therefore, there is strong evidence to support uNK cell's "reviled and revered" behavior in pregnancy. However, whether uNK cells dual role in the pregnant uterus is the result of a single multifunctional cell, or multiple uNK cell subsets remains as a challenging question in reproductive immunology. Keywords: Mouse uNK cell function, Mouse uNK cell phenotype, Mouse uNK cell life-cycle, mesometrial lymphoid aggregate of pregnancy (MLAp). I –
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