Dose-dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy.

PROBLEM: Systemic maternal inflammation is associated with adverse neonatal sequelae. We tested the hypothesis that IL-1beta is a key inflammatory regulator of adverse pregnancy outcomes. METHOD OF STUDY: Pregnant mice were treated with intraperitoneal injections of IL-1beta (0, 0.1, 0.5, or 1 mug) from embryonic day (E)14 to E17. Placenta and fetal brains were harvested and analyzed for morphologic changes and IL-1beta signaling markers. RESULTS: As compared with non-treated dams, maternal injections with IL-1beta resulted in increased p-NF-kappaB and caspase-1 in placentas and fetal brains, but not consistently in spleens, suggesting induction of intrinsic IL-1beta production. These findings were confirmed by increased levels of IL-1beta in the placentas of the IL-1beta-treated dams. Systemic treatment of dams with IL-1beta suppressed Stat1 signaling. Maternal inflammation caused by IL-1beta treatment reduced fetal viability to 80.6% and 58.9%, in dams treated with either 0.5 or 1 mug of IL-1beta, respectively. In the placentas, there was an IL-1beta dose-dependent distortion of the labyrinth structure, decreased numbers of mononuclear trophoblast giant cells, and reduced proportions of endothelial cells as compared to placentas from control dams. In fetal brains collected at E17, there was an IL-1beta dose-dependent reduction in cortical neuronal morphology. CONCLUSION: This work demonstrates that systemic IL-1beta injection causes dose-dependent structural and functional changes in the placenta and fetal brain.