Regulation of Interleukin-6 Expression in Human Decidual Cells and Its Potential Role in Chorioamnionitis

Abstract

Chorioamnionitis frequently precedes both genital tract and placental inflammation and is both a primary cause of maternal morbidity and a major antecedent of preterm premature rupture of the membranes (PPROM) as well as preterm delivery (PTD). In most cases of chorioamnionitis , neutrophils dominate the decidua. In a subset of these cases , a predominance of monocytes is uniquely associated with both neonatal intraventricular hemorrhage and death. The multifunctional cytokine , interleukin-6 , promotes local monocyte dominance via several mechanisms. In this study , immunostaining of placental sections revealed significantly higher interleukin-6 HSCOREs in decidual cells (DCs) but not in interstitial trophoblasts , in chorioamnionitis versus gestational agematched control placentas (P < 0.05). In confluent leukocyte-free term DCs , secreted interleukin-6 levels in incubations with estradiol-17␤ were increased 2500-fold by IL-1␤ (P < 0.05). This up-regulation was inhibited by more than 50% in parallel incubations that included medroxyprogesterone acetate (n ‫؍‬ 12, P < 0.05). Western blotting data confirmed these enzyme-linked immunosorbent assay results; quantitative RT-PCR findings demonstrated corresponding changes in interleukin-6 mRNA levels. Specific inhibitors of signaling for both nuclear factor-B activation and p38-mitogen-activated protein kinase , but not for protein kinase C , significantly decreased IL-1␤-enhanced interleukin-6 expression levels in cultured DCs. In conclusion , in situ and in vitro results indicate that significantly enhanced interleukin-6 expression levels in DCs during chorioamnionitis could be pivotal in skewing decidual monocyte differentiation to macrophages.

Decidualization Mediated by Steroid Hormones Modulates the Innate Immunity in Response to Group B Streptococcal Infection in vitro

“…This is in agreement with previous reports showing that IL-6 is secreted by decidual cells under non-infectious conditions [32,33], chorioamnionitis [34], and decidual primary cultures from women who underwent preterm labor with subclinical intrauterine infection [25,35]. Although it has been described that E 2 and P 4 downregulate some inflammatory markers in different cell types [25], in our model, decidual IL-6 secretion was not depleted by hormones as it was previously reported by Lockwood et al [34]. This discrepancy may be due to differences in hormone concentration and/or decidualization time.…”

“…This discrepancy may be due to differences in hormone concentration and/or decidualization time. In the same work, the addition of the pro-inflammatory cytokine IL-1β to hormonal-stimulated decidual cells results in enhanced secretion of IL-6 [34], but apparently in our model, IL-6 secretion is not dependent of IL-1β, because our experiments show that IL-1β is not secreted even under infection conditions. However, in our model, the presence of GBS as inflammatory stimulus triggers IL-6 production in DSCs, suggesting a leading role of this cytokine in the pro-inflammatory network elicited by gestational tissues during intrauterine infection.…”

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

“…Other studies have demonstrated high levels of production of IL6 by BeWo cells and its involvement in the endocrine properties of these cells [22,72]. However, this cytokine should be at adequate concentrations at the maternal-fetal interface because high levels of IL6 are associated with preeclampsia and inflammatory processes in the amnion [73,74]. Thus, it is plausible that TGFB1 and IL10 down-modulate IL6 release in order to control the level of this cytokine in BeWo cells, which in turn, promotes the increased proliferation of T. gondii, allowing dissemination of the infection in our model.…”

Compartmentalization of acute phase reactants Interleukin-6, C-Reactive Protein and Procalcitonin as biomarkers of intra-amniotic infection and chorioamnionitis

“…Studies genotyping the amniochorion neutrophils demonstrated that the initial inflammatory response is maternal in its origin [ 19, 20, 21 ]. It remains unknown why the initial wave of decidual inflammation [ 22 ] is not associated with signs and symptoms of maternal clinical chorioamnionitis (i.e. fever, maternal leukocytosis).…”