Maternal regulation of placental trophoblast proliferation by decidual interleukin-1 (IL-1)

The maternal immune response to the fetus during early pregnancy is characterized by an influx of maternal immune cells to the maternal-fetal interface. The activation of these cells is evident by the production of inflammatory cytokines within maternal decidua. In mice, these maternal-derived inflammatory cytokines function as growth factors for fetal placental trophoblast, which has led to the development of the Immunotrophism Hypothesis. In humans, the pro-inflammatory cytokine IL-1 is expressed in maternal decidua; however, its function in the regulation of placental growth has not been elucidated. Thus, the role of IL-1 in the regulation of human placental trophoblast proliferation was explored in these studies.; Using Northern blot analysis, IL-1β mRNA expression was found only in maternal decidua, but not fetal placental villi. Tissue extractable IL-1 protein, similar to IL-1β mRNA expression, was high in decidua, but not in the placenta. These finding demonstrate that maternal decidua is a major source of IL-1 production during early pregnancy and suggests that IL-1 could regulate placental trophoblast proliferation in a paracrine fashion. The ability of IL-1 to stimulate trophoblast proliferation was assessed by in vitro proliferation studies in human invasive trophoblast (ED ₂₇, ED₃₁, ED₇₇, and HTR8/SVneo) and villous cytotrophoblast (Jar and BeWo) cell lines. In these studies, IL-1 was found to stimulate invasive trophoblast and inhibit villous cytotrophoblast proliferation.; The mechanisms involved in IL-1 stimulation of invasive trophoblast proliferation were further studied. IL-1 induced trophoblast and placental villous core mesenchymal cell production of gp130 ligands (IL-6 and LIF), which in turn stimulate trophoblast proliferation. IL-1 signal transduction in trophoblast was determined using Western Blot Analysis. IL-1 treatment in trophoblast cell lines leads to the activation of NF-κB, PI3K, p38 MAPK, p44/p42 MAPK and SAPK/JNK pathways. Inhibitors for these pathways caused a significant decrease in IL-1-induced trophoblast proliferation and IL-6 production. In conclusion, maternal decidual IL-1 activation of specific signal transduction pathways stimulates invasive trophoblast proliferation directly, and through the induction of gp130 ligands.