Preeclampsia-related increase of interleukin-11 expression in human decidual cells

Abstract

Preeclampsia is associated with increased systemic inflammation and superficial trophoblast invasion, which leads to insufficient utero-placental blood flow. Interleukin (IL)-11 mediates pro- and anti-inflammatory processes and facilitates decidualization. To identify IL-11 expression in vivo at the maternal-placental interface in preeclampsia and control specimens and evaluate regulatory effects of TNF (tumor necrosis factor)-α and IL-1β, cytokines elevated in preeclampsia, on IL-11 levels in first trimester decidual cells in vitro. Placental sections were immunostained for IL-11. Leukocyte-free first trimester decidual cells were incubated with estradiol (E2) ±10−7 mol/L medroxyprogesterone acetate (MPA) ± TNF-α or IL-1β ± inhibitors of the p38MAPK, nuclear factor-kappa B (NFκB), or protein kinase C (PKC) signaling pathways. An ELISA assessed secreted IL-11 levels, and quantitative RT-PCR measured IL-11 mRNA. IL-11 immunoreactivity in placental sections was significantly higher in the cytoplasm of preeclamptic decidual cells versus gestational age-matched controls. Compared to decidual cells, IL-11 immunostaining in neighboring trophoblast is lower, perivascular and not different between control and preeclamptic specimens. TNF-α and IL-1β enhanced levels of IL-11 mRNA and secreted IL-11 in cultured decidual cells. Specific inhibitors of the p38 MAPK and NFκB but not PKC signaling pathways reduced the stimulatory effect of IL-1β. Expression of decidual IL-11 is increased in preeclampsia and suggests a role for IL-11 in the pathogenesis of preeclampsia.

Interleukin-11 alters placentation and causes preeclampsia features in mice

“…IL11 protein was also significantly increased in human PE villous and EVT. This supports a previous study demonstrating increased decidual IL11, but contradicts reported unchanged IL11 levels in EVT in PE at term, relative to gestation matched controls (20), likely due to population and/or methodological differences.…”

“…S2), implying a role in placentation in vivo. To model elevated levels of IL11 as in women with PE (20), mice were administered with physiologically relevant doses of IL11 (Fig. S3) or saline vehicle control twice daily from embryonic day (E)8 through E13 to determine effects on spiral artery remodeling and placentation (22), or E10 through E17 to determine effects on PE features.…”

“…IL11 is required for decidualization in humans (18) and mice (19). IL11 levels are elevated in PE decidual tissue (20). More recently, IL11 has been shown to impede human EVT invasion in vitro (16,21), although its function in placentation in vivo has not been investigated.…”

The role of interleukins in preeclampsia: A comprehensive review

“…The PE decidual cell samples stained significantly more positively than control for IL‐11, while PE trophoblasts also stained more positively but not in a statistically significant way. The role of IL‐11 in pregnancy complications was also strengthened by the fact that addition of IL‐1 and TNF‐α lead to increased IL‐11 expression in first‐trimester‐cultured decidual cells, derived from electively terminated gestations …”

The presence of heparins during decidualization modulates the response of human endometrial stromal cells to IL-1β in vitro

“…During the decidualization of the endometrial stroma in the second half of the cycle, IL-11 has been shown to be an important autocrine promoter of progesterone-induced differentiation [27]. However, it has also been shown that decidual IL-11 is increased by IL-1β in preeclampsia, suggesting a role for IL-11 in the pathogenesis of preeclampsia [28]. The maximal expression of IL-6 in the human endometrium is seen in the mid-secretory phase and at menstruation [6].…”