Title: Maternal Regulation of Trophoblast Proliferation by Decidual Interleukin-1 (IL-1)
Abstract: Objectives: According to the Immunotrophism Hypothesis, inflammatory cytokines produced by activated maternal decidual immune cells act as growth factors for the placenta. We have previously shown that the inflammatory cytokine IL-1 is upregulated in maternal decidua during early human pregnancy. Consequently, the objectives of this study were to determine if decidual IL-1 provides a unique maternal mechanism for the regulation of trophoblast proliferation during early pregnancy. Design: Prospective determination of matched decidual and placental samples for IL-1 expression. In vitro study of trophoblast proliferation by recombinant IL-1 and decidual conditioned media. Materials and Methods: Matched decidual and placental tissues (N=10) from normal first and second trimester pregnancies were examined for IL-1 mRNA expression by Northern analysis and immunoreactive IL-1β and IL-1α protein by ELISA. Decidual explants (N=6) were cultured in DMEM/F12 for 48 hours and the decidual conditioned media assayed by ELISA for IL-1β and IL-1α production. First trimester human trophoblast cell lines (ED27, ED31, ED77) were examined for IL-1 receptor type I (IL-1RI) expression by RT-PCR, and IL-1β and IL-1α production by ELISA. The proliferative response of ED27, ED31, ED77 trophoblast cells to IL-1β and decidual conditioned media was performed using a MTT proliferation assay. Results: IL-1β mRNA was highly expressed in decidual tissues but not expressed in matched placental tissues. Tissue levels of IL-1β and IL-1α protein were significantly higher in decidua compared to placenta (twenty and six-fold respectively, P<0.001). In addition, decidua secreted physiologic levels of IL-1β (190 pg/ml/24 hours), but not IL-1α into the media. Similar to normal placenta, ED27, ED31, and ED77 trophoblast cells expressed IL-1RI mRNA but did not produce IL-1α or IL-1β. Recombinant IL-1β treatment stimulated trophoblast proliferation in a dose dependent manner at concentrations as low as 10 pg/ml. In addition, decidual conditioned media significantly stimulated trophoblast proliferation that could be inhibited by IL-1β neutralizing antibody in a dose dependent manner. Conclusions: These studies demonstrate that IL-1 is produced and secreted by the maternal decidua, but not the placenta, during normal early human pregnancy. Furthermore, maternal decidua IL-1 stimulates fetal trophoblast proliferation. Consequently, these studies demonstrate that IL-1 provides a unique mechanism for the maternal regulation of trophoblast proliferation and supports the Immunotrophism Hypothesis during early human pregnancy.