The physiological role of interleukin-6 in the placenta and its pathological potential in pregnancy

Summary. Interleukin-6 (IL-6) is a pleiotropic cytokine with pro-inflammatory and anti-inflammatory functions. Placentation and pregnancy progression depend on adequate interaction between the processes of proliferation, apoptosis, and invasion of trophoblast cells into the endometrium. Various cytokines and growth factors play important roles in regulating these processes, where IL-6 represents one of the major regulatory molecules influencing the trophoblast phenotype. In physiological circumstances, IL-6 is involved in angiogenesis and remodeling of endometrial blood flow, stimulates the production of placental hormones, and is one of the main regulators of inflammation response and immune homeostasis in the placenta. Elevated levels of IL-6 are indicated in women with infertility, preeclampsia, and placental neoplastic processes. Hypoxic conditions in the placenta play a pivotal role in modulating differentiation, invasion, and redox homeostasis of trophoblast and also seems to have a  significant contribution to IL-6 effects. At the same time, IL-6 affects the oxidative state of trophoblasts, although the mechanisms of these outcomes are yet to be fully understood. Our experiments suggest the importance of hypoxic conditions in determining the effects of IL-6 in trophoblasts and the differential reactivity of JEG-3 cells in response to this cytokine. Additionally, increased levels of IL-6 in different systemic pathological states induce various disturbances of trophoblast cell homeostasis and could be one of the risk factors in the development of pregnancy disorders. Recently, increased IL-6 levels have been detected in COVID-19 cases as one of the major actors of the cytokine storm, raising the concerns of infection regarding the effects on the placenta and the offspring.