HUMAN PLACENTAL CYTOTROPHOBLASTS PRODUCE THE IMMUNOSUPPRESSIVE CYTOKINE INTERLEUKIN-10

The mechanism by which the mammalian mother accepts the implanting fet us as all allograft remains unexplained, but is likely to be the resul t of a combination of factors. Mononuclear cytotrophoblasts, the speci alized fetal cells of the placenta that invade the uterus, play an imp ortant role. These cells express HLA-G, an unusual major histocompatib ility complex class I-B molecule, and secrete cytokines and pregnancy- specific proteins that can function. We investigated whether cytotroph oblasts secrete interleukin 10 (IL-10), a cytokine that potently inhib its alloresponses in mixed lymphocyte reactions. Cytotrophoblasts from all stages of pregnancy produced IL-10 in vitro, but neither placenta l fibroblasts nor choriocarcinoma (malignant trophoblast) cell lines d id so. Spontaneous IL-10 production averaged 650, 853, and 992 pg/10(6 ) cells in the first, second, and third trimesters of pregnancy, respe ctively. IL-10 secretion dropped similar to 10-fold after the first 24 h of culture, and was paralleled by a decrease in messenger RNA. IL-1 0 messenger RNA was detected in biopsies of the placenta and the porti on of the uterus that contains invasive cytotrophoblasts, suggesting t hat this cytokine is also produced in vivo. IL-10 secreted by cytotrop hoblasts in vitro is bioactive, as determined by its ability to suppre ss interferon gamma production in an allogeneic mixed lymphocyte react ion. We conclude that human cytotrophoblast IL-10 may be an important factor that contributes to maternal tolerance of the allogeneic fetus.