Interleukin (IL)-6: A Friend or Foe of Pregnancy and Parturition? Evidence From Functional Studies in Fetal Membrane Cells

Abstract

Objective: Protection of the fetus within the amniotic sac is primarily attained by remodeling fetal membrane (amniochorion) cells through cyclic epithelial to mesenchymal and mesenchymal to epithelial (EMT and MET) transitions. Endocrine and paracrine factors regulate EMT and MET during pregnancy. At term, increased oxidative stress forces a terminal state of EMT and inflammation, predisposing to membrane weakening and rupture. IL-6 is a constitutively expressed cytokine during gestation, but it is elevated in term and preterm births. Therefore, we tested the hypothesis that IL-6 can determine the fate of amnion membrane cells and that pathologic levels of IL-6 can cause a terminal state of EMT and inflammation, leading to adverse pregnancy outcomes. Methods: Primary amnion epithelial cells (AECs) were treated with recombinant IL-6 (330, 1,650, 3,330, and 16,000 pg/ml) for 48 h (N = 5). IL-6-induced cell senescence (aging), cell death (apoptosis and necrosis), and cell cycle changes were studied using flow cytometry. Cellular transitions were determined by immunocytochemistry and western blot analysis, while IL-6 signaling (activation of signaling kinases) was measured by immunoassay. Inflammatory marker matrix metalloproteinase (MMP9) and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations were measured using a Fluorokine E assay and ELISA, respectively. Amniotic membranes collected on gestational day (D) 12 and D18 from IL-6 knockout (KO) and control C57BL/6 mice (N = 3 each) were used to determine the impact of IL-6 on cell transitions. Fold changes were measured based on the mean of each group. Results: IL-6 treatment of AECs at physiologic or pathologic doses increased JNK and p38MAPK activation; however, the activation of signals did not cause changes in AEC cell cycle, cellular senescence, apoptosis, necrosis, cellular transitions, or inflammation (MMP9 and GM-CSF) compared to control. EMT markers were higher on D18 compared to D12 regardless of IL-6 status in the mouse amniotic sac.

Actions of Bisphenol A on Different Feto-Maternal Compartments Contributing to Preterm Birth

“…In rhesus monkeys, for instance, IL-1β stimulates IL-17 production from chorioamniotic T-cells, propagating the inflammatory response in these layers [ 61 ]. On the other hand, IL-6, on its own, does not induce any inflammatory and cellular transition changes in AECs [ 117 ]. However, IL-6 stimulates the production of PGE2 with a concomitant decrease in PGDH in AECs, increasing prostaglandins within the fetal membranes especially with a continuous influx of IL-6 from other feto-maternal units [ 118 ].…”

Functional role and regulation of permeability‐glycoprotein (P‐gp) in the fetal membrane during drug transportation

“…54 This finding indirectly supports a prior report by Richardson et al that amnion mesenchymal cells are transitioned epithelial cells and not necessarily permanent constituents. 55,56,54 They are seen in the extracellular matrix during their transient state to become epithelial cells again. 14 During this state of cyclic transition, cells do not express markers that are expressed by primary cells (i.e., amnion epithelial cells) and do not perform similar functions.…”

Combined Effects of Methyldopa and Flavonoids on the Expression of Selected Factors Related to Inflammatory Processes and Vascular Diseases in Human Placenta Cells—An In Vitro Study

“…Numerous reports indicate that the plasma of preeclamptic patients contains elevated levels of IL-6, a multifunctional cytokine that regulates, among other things, the acute phase reaction and modulates both pro- and anti-inflammatory events, and may play roles in the pathogenesis of preeclampsia by serving as a source of a key circulating factor that promotes systemic maternal endothelial cell dysfunction [ 55 ]. Additionally, while many of the functions of IL-6 have not been explained yet, it is assumed that IL-6 is a good biomarker for adverse pregnancies [ 56 ]. In this study it was found that all tested compounds, i.e., methyldopa and all flavonoids, increased mRNA IL-6 expression, but every combined administration of a flavonoid together with methyldopa showed a strong contrary inhibitory effect when compared to the value for methyldopa in JEG-3 cells.…”