Endotoxin-induced chorioamnionitis modulates innate immunity of monocytes in preterm sheep

The preterm fetus is immune naive and has immature innate immune function. Although the preterm fetus is frequently exposed to chorioamnionitis, the effects of exposure of the fetal lung to inflammation on innate immune responses are unknown. Using the fetal sheep model of chorioamnionitis, cord blood monocytes were isolated from preterm lambs 1 to 14 days after intra-amniotic endotoxin injection, cultured for approximately 16 hours, and challenged with endotoxin in vitro. Compared with monocytes from adult sheep, the preterm monocytes produced less H2O2 and interleukin-6, and toll-like receptor 4 expression was decreased. Three days after intra-amniotic enclotoxin exposure, preterm monocyte responses to in vitro enclotoxin challenge demonstrated decreased H2O2 and interleukin-6 production and decreased CD14 and major histocompatibility complex class 11 expression. Preterm monocyte responses 7 to 14 days after enclotoxin tended to exceed those of adults and preterm control animals indicating augmented function. In contrast, a second intra-amniotic enclotoxin injection 7 days after the initial enclotoxin exposure suppressed monocyte function at 14 days. The fetal monocytes demonstrated patterns of responses consistent with enclotoxin tolerance (immune paralysis) as well as maturation of function. Modulation of fetal innate immune responses by exposure to inflammation may alter subsequent immune adaptation after birth.