Blocking of the placental immune-modulatory ferritin activates Th1 type cytokines and effects placenta development, fetal growth and the pregnancy outcome

Background: Placenta immunomodulatory ferritin (PLIF) cDNA was recently cloned from the human placenta, where it is expressed in syncytiotrophoblast and decidual mononuclear cells. PLIF and its subcloned bioactive domain (C48), expressed in Escherichia coli, are immunosuppressive proteins and induce pronounced IL-10 production in vitro and in vivo. Methods and Results: PLIF serum level, measured by enzyme-linked immunosorbent assay, was elevated in pregnant mice throughout gestation and declined towards delivery. Blocking of PLIF activity by vaccination of mice with C48 prior to mating inhibited pregnancy development. Passive transfer of anti-C48 immunoglobulin (Ig) starting at 3.5-12.5 days post coitum (dpc) resulted in high rate of embryo resorption. Furthermore, treatment with anti-C48 Ig resulted in placental and embryonal growth restriction. At gestation day 13.5, growth retardation was especially notable in the placentae, while at 16.5 dpc it was pronounced in the embryos. Histopathological examination revealed that experimental placentae were globally hypoplastic and the labyrinth was strikingly pale and contained less maternal blood compared with control. Immune-activated spleen cells harvested at 13.5 dpc from anti-C48 Ig-treated pregnant mice secreted in vitro increased level of Th1 cytokines (IL-2, TNF-α, IL-12) and decreased level of Th2 cytokines (IL-10, IL-4, IL-5, IL-6) as compared with the level of the respective cytokines secreted by spleen cells from control pregnant mice. Conclusion: This study provides the first in vivo evidence that PLIF plays a major role in placentation and embryonic growth.