Trophoblast invasion and modification of the spiral arterioles are essential for the establishment of adequate uteroplacental blood flow during pregnancy. However, such vascular remodeling is deficient in preeclampsia. This disease is also associated with increased maternal levels of circulating proinflammatory cytokines such as tumor necrosis factor (TNF) and reduced levels of immunoregulatory cytokines such as interleukin 10 (IL10). We have previously shown that activated macrophages inhibit trophoblast invasiveness in vitro. The present study demonstrates that IL10 interferes with the invasion-inhibitory effect that activated macrophages exert on trophoblast cells. Co-culture experiments revealed that human lipopolysaccharide (LPS)-activated macrophages inhibited the ability of immortalized HTR-8/SVneo human trophoblast cells to invade through reconstituted extracellular matrix. This effect of activated macrophages on trophoblast invasiveness was paralleled by decreased expression of urokinase plasminogen activator receptor (PLAUR) on the surface of trophoblast cells, and by increased secretion of plasminogen activator inhibitor type 1 (SERPINE1). Exposure of LPS-treated macrophages to IL10 prior to co-culture prevented their ability to inhibit trophoblast invasion, PLAUR expression, and to stimulate SERPINE1 secretion. Interleukin 10 prevented macrophage activation by LPS as determined by the lack of secretion of TNF in the culture medium, and a neutralizing TNF antibody completely blocked the effect of macrophages on trophoblast invasion. These results indicate that decreased circulating levels of IL10 associated with preeclampsia may contribute to inadequate trophoblast invasion and remodeling of the uterine spiral arterioles.