IL-10 Modulates Placental Responses to TLR Ligands

Department of Pediatrics-Neonatology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
American Journal Of Reproductive Immunology (Impact Factor: 2.44). 10/2009; 62(6):390-9. DOI: 10.1111/j.1600-0897.2009.00756.x
Source: PubMed


Intra-uterine infections increase production of pro-inflammatory cytokines. It is unclear whether different infectious agents determine the relative expression of pro-and anti-inflammatory cytokines.
We compared the placental inflammatory response induced by bacterial lipopolysaccharide (LPS, endotoxin from Gram-negative bacteria) with those induced by lipoteichoic acid (LTA, a cell wall component of Gram-positive bacteria). Placental explants from term delivery were treated with either LPS or LTA, in the presence or absence of IL-10, for 24 hrs. Cytokines, prostaglandin E(2) (PGE(2)) production and cyclo-oxygenase-2 (COX-2) expression were quantified.
Both LTA and LPS significantly induced several cytokines with LPS eliciting more potent effects. IL-6 and IL-8 were induced to comparable levels in response to both LTA and LPS whereas monocyte chemotactic protein-1 (MCP-1) production was induced more by LTA, demonstrating a differential placental response to a specific toll-like receptor (TLR) ligand. IL-10 treatment significantly reduced most pro-inflammatory cytokines as well as PGE(2) induced by both LPS and LTA. Interestingly, IL-10 down-regulated LTA-mediated MCP1 induction, but not that mediated by LPS. Moreover, IL-10 was more effective in down-regulating PGE(2) after LPS- when compared with LTA stimulation.
Our results demonstrate that placental exposure to LTA and LPS appear to trigger distinct cytokine responses that can be modulated by IL-10.

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    • "Finally, the classical anti-inflammatory cytokine IL-10 in this model was investigated. Use of this cytokine has been proposed as a treatment for PTL (Robertson et al., 2006; Bayraktar et al., 2009), and it is increased in amniotic fluid of women in PTL (Gotsch et al., 2008). Whilst IL-10 co-treatment had no significant effect on LPS-induced IL-6 and IL-8 secretion from PHM1-41 cells (Fig. 8A and D), the IL-6 and IL-8 releases in both LPS treated primary monocytes (P , 0.01 and P , 0.05, Fig. 8B and E) and PHM1-41/monocyte co-cultures were inhibited by IL-10 (P , 0.01 and P , 0.05, Fig. 8C and F). "
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    ABSTRACT: Both term and preterm parturition are characterised by an influx of macrophages and neutrophils into the myometrium and cervix, with co-incident increased peripheral blood monocyte activation. Infection and inflammation are strongly implicated in the pathology of preterm labour (PTL), with progesterone considered a promising candidate for its prevention or treatment. In this study, we investigated the effect of monocytes on myometrial smooth muscle cell inflammatory cytokine production both alone and in response to LPS, a TLR4 agonist used to trigger PTL in vivo. We also investigated the effect of monocytes on myocyte contraction. Monocytes, isolated from peripheral blood samples from term pregnant women, were cultured alone, or cocultured with PHM1-41 myometrial smooth muscle cells, for 24h. In a third set of experiments, PHM1-41 myocytes were cultured for 24h in isolation. Cytokine secretion was determined by ELISA or multiplex assays. Coculture of monocytes and myocytes led to synergistic secretion of pro-inflammatory cytokines and chemokines including IL-6, IL-8 and MCP-1, with the secretion being further enhanced by LPS (100ng/ml). The synergistic secretion of IL-6 and IL-8 from cocultures was mediated in part by direct cell-cell contact, and by TNF. Conditioned media from cocultures stimulated contraction of PHM1-41 myocytes, and the effect was inhibited by progesterone. Both progesterone and IL-10 inhibited LPS-stimulated IL-6 and IL-8 secretion from cocultures, while progesterone also inhibited chemokine secretion. These data suggest that monocytes infiltrating the myometrium at labour participate in crosstalk that potentiates pro-inflammatory cytokine secretion, an effect that is enhanced by LPS and can augment myocyte contraction. These effects are all partially inhibited by progesterone.
    Molecular Human Reproduction 05/2015; 21(8). DOI:10.1093/molehr/gav027 · 3.75 Impact Factor
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    • "These include IL-4, IL-10 and IL-13. IL-10 can down-regulate LPS-and LTA-induced cytokine/chemokine responses by the healthy term placenta (Bayraktar, Peltier et al. 2009). Paradoxically, IL-10 is increased in amniotic fluid from women in term labour and women with intra-amniotic infection at term and preterm, and is also increased in those without infection who delivered preterm rather than term (Gotsch, Romero et al. 2008). "
    Recent Advances in Research on the Human Placenta, 03/2012; , ISBN: 978-953-51-0194-9
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    • "Recognizing that there are other anti-inflammatory factors, some investigators have established balance sheets that attempt to determine if broad panels of cytokines favor pro- or anti-inflammatory cytokines. One report indicated a 7-fold increase in preterm birth (before 34 weeks) risk when a high inflammatory to anti-inflammatory ration was detected [78]. Other studies agree, indicating that most pro-inflammatory cytokines are increased in preterm birth, while anti-inflammatory cytokines are decreased [79], and specifically in the cervix the pro-inflammatory versus anti-inflammatory score predominated [80]. "
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    ABSTRACT: The uterine cervix plays a vital role in maintaining pregnancy and an equally important role in allowing parturition to occur. Progesterone, either endogenously produced or supplied exogenously, supports the function of the cervix in sustaining intrauterine pregnancy, and the withdrawal of progesterone, either through natural processes or pharmacologic intervention, leads to delivery which underscores the importance of the progesterone's biological activities manifest in normal gestation and pregnancy that ends prematurely. Research crossing many scientific disciplines has demonstrated that progesterone is a pleotropic compound that affects the cervix through cytoplasmic and membrane receptors with profound effects on cellular and molecular functions that influence inflammatory cascades and extracellular matrix, both of which have consequences for parturition. Beyond the local cell and molecular biology of progesterone, it has systemic effects of relevance to pregnancy as well. This paper examines the biology of the cervix from its gross to cellular structure and biological activities of its cell and molecular processes that may be affected by progesterone. The implications of these processes for preterm birth are explored, and direction of current research is in relation to translational medicine implications for diagnostic, prognostic, and therapeutic approaches to threatened preterm birth.
    Infectious Diseases in Obstetrics and Gynecology 10/2011; 2011(1064-7449):353297. DOI:10.1155/2011/353297
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