Interleukin‐1 family cytokines and their regulatory proteins in normal pregnancy and pre‐eclampsia
Maternal systemic inflammation is a feature of pre‐eclampsia, a condition in pregnancy characterized by hypertension and proteinuria. Pre‐eclampsia is caused by the placenta; many placental factors contribute to the syndrome's progression, and proinflammatory cytokines have been identified previously as one such mediator. The interleukin (IL)‐1 family of cytokines are key regulators of the inflammatory network, and two naturally occurring regulatory molecules for IL‐1 family cytokines, IL‐1RA and sST2, have been found previously to be elevated in maternal blood from women with pre‐eclampsia. Here we investigate more recently identified IL‐1 family cytokines and regulatory molecules, IL‐1RAcP, IL‐37, IL‐18BP, IL‐36α/β/γ/Ra and IL‐38 in pre‐eclampsia. Pregnant women have more circulating IL‐18BP and IL‐36Ra than non‐pregnant women, and sIL‐1RAcP is elevated from women with pre‐eclampsia compared to normal pregnancies. The placenta expresses all the molecules, and IL‐37 and IL‐18BP are up‐regulated significantly in pre‐eclampsia placentas compared to those from normal pregnancies. Together, these changes contribute to the required inhibition of maternal systemic cytotoxic immunity in normal pregnancy; however, in pre‐eclampsia the same profile is not seen. Interestingly, the increased circulating levels of sIL‐1RAcP and increased placental IL‐18BP and IL‐37, the latter of which we show to be induced by hypoxic damage to the placenta, are all factors which are anti‐inflammatory. While the placenta is often held responsible for the damage and clinical symptoms of pre‐eclampsia by the research community, here we show that the pre‐eclampsia placenta is also trying to prevent inflammatory damage to the mother.