IL-1 family members regulate innate immune responses, are produced by gestation-associated tissues, and have a role in healthy and adverse pregnancy outcomes. To better understand their role at the materno-fetal interface we used a human tissue explant model to map lipopolysaccharide (LPS)-stimulated production of IL-1α, IL-1β, IL-18, IL-33, IL-1Ra, IL-18BPa, ST2 and IL-1RAcP by placenta, choriodecidua and amnion. Caspase-dependent processing of IL-1α, IL-1β, IL-18, and IL-33 and the ability of IL-1α, IL-1β, IL-18, and IL-33 to regulate the production of IL-1RA, IL-18BPa, ST2 and IL-1RAcP was also determined. LPS acted as a potent inducer of IL-1 family member expression especially in the placenta and choriodecidua with the response by the amnion restricted to IL-1β. Caspases-1, 4 and 8 contributed to LPS-stimulated production of IL-1β and IL-18, whereas calpain was required for IL-1α production. Exogenous administration of IL-1α, IL-1β, IL-18, and IL-33 lead to differential expression of IL-1Ra, IL-18BPa, ST2 and IL-1RAcP across all tissues examined. Most notable were the counter-regulatory effect of LPS on IL-1β and IL-1Ra in the amnion and the broad responsiveness of the amnion to IL-1 family cytokines for increased production of immunomodulatory peptides and soluble receptors. The placenta and membranes vary not only in their output of various IL-1 family members but also in their counter-regulatory mechanisms through endogenous inhibitory peptides, processing enzymes and soluble decoy receptors. This interactive network of inflammatory mediators likely contributes to innate defence mechanisms at the materno-fetal interface to limit, in particular, the detrimental effects of microbial invasion.

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Maternal obesity has been implicated in adverse pregnancy outcomes such as miscarriage, preeclampsia and gestational diabetes mellitus (GDM) and poses a risk to the neonate. There is a knowledge gap surrounding obesity and changes to the maternal immune system. Hypothesis: Obesity exacerbates systemic inflammation in pregnant women at 28 weeks of gestation. Samples: Peripheral blood was collected from fasted women at 26–28 weeks of gestation; all were GDM-negative Results: Insulin (p=<0.0001) and PAI-1 (p=0.0487) levels were increased in obese versus non-obese pregnant women. Obese women had a relative neutrophilia (p=0.0429) accompanied by diminished eosinophil (p=0.0178) and NKT cell (p=0.0124) numbers. The inflammatory cytokine profile of MNCs was mostly unchanged with obesity but the Th profile of pregnant women with obesity appears skewed towards Th17: on stimulation with CytoStim™, IL-6 (p=0.0183), TNFα (p=0.0478), IL-17F (p=0.0183) and IL-22 (p=0.0183) levels were increased; Th2 cells (p=0.0250) were also reduced with maternal obesity. Monocyte phenotypes showed some changes with obesity; on intermediate monocytes, CD86 (p=0.0068) was decreased yet CD163 (p=0.0421) was increased, and CCR2 expression was elevated on classical (p=0.0040) and intermediate (p=0.0340) monocytes. There is a shift to Th1 and Th17 in obesity in the general populations, whereas pregnancy is associated with a shift to Th2 and Treg. Here, we show that this profile is compromised in maternal obesity, which might underpin detrimental effects on pregnancy. Further research should investigate homogenous populations of cells such as eosinophils, monocytes and T cells, to further understand the immunological consequences of maternal obesity.