The establishment of a functional placenta is integral for normal fetal development and the maintenance of pregnancy. In the course of placentation, trophoblast progenitors differentiate into highly invasive trophoblast subtypes that infiltrate the uterine wall, where they transform spiral arteries to establish an uteroplacental blood circulation. This differentiation process towards an invasive phenotype is tightly controlled by a diversity of factors. One case in point is the highly complex pregnancy-related cytokine network that likely modulates trophoblast behavior. Notably, altered cytokine levels have been observed in pregnancy disorders such as preeclampsia, resulting from insufficient trophoblast invasion. Yet, little is known about the direct effects cytokines exert on trophoblasts.
This thesis project aimed to elucidate the role of interleukin (IL)-1 family members, namely IL-1[beta] and IL-33, during early human placental development. In the past, pregnancy-related functions have been ascribed to both cytokines. While IL-1[beta] has emerged as important player during blastocyst implantation, its effect on placentation and trophoblast invasion has not been conclusively answered and was therefore re-evaluated in this project. IL-33 is a potent mediator of type-2 cytokine responses, which are central for the maintenance of pregnancy. Notably, elevated serum levels of soluble ST2, the natural inhibitor of IL-33, have been recently reported in patients with preeclampsia. However, the role of the IL-33/ST2 axis during healthy pregnancy remained elusive and was thus approached in this thesis. Descriptive analyses showed strong expression of the IL-1 receptor by human trophoblasts. Treatment with recombinant IL-1[beta] significantly induced invasion of primary trophoblasts and trophoblast outgrowth in placental explant cultures. In the presence of IL-1[beta], secretion of the invasion-associated protease urokinase was remarkably upregulated in both model systems. The IL-33 receptor ST2L also localized to various trophoblast subtypes, whereas IL-33 was detected in the cytoplasm of placental and decidual macrophages. ELISA analysis revealed the active secretion of IL-33 by both macrophage populations. Recombinant IL-33 strongly enhanced BrdU incorporation into primary trophoblasts and this effect was also seen in placental explant cultures. Finally, IL-33-dependent proliferation was found to be mediated via PI3K/AKT and MAPK/ERK signaling pathways. Altogether, these findings highlight the vital impact of the IL-1 family on trophoblast invasion and placental growth during early pregnancy.