Placental growth factor enhances inflammatory toll-like receptor responses in syncytiotrophoblasts

Pregnancy requires that the development of immune tolerance to avoid fetal rejection is balanced with functional immune surveillance mechanisms against infectious pathogens. Trophoblast cells play a unique role in influencing the state of maternal and fetal immune activation. Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, is a placental-derived factor with maximal expression during early third trimester, when women are at particular risk of morbidity from viral infections. Having previously demonstrated that PlGF enhanced toll-like receptor (TLR)-mediated inflammatory cytokine expression in peripheral blood mononuclear phagocytes, we hypothesized that PlGF might also contribute to hyper-inflammatory TLR responses in the trophoblast.

Primary human syncytiotrophoblast cells were cultured in the presence of VEGF receptor-1 (VEGFR1) ligands (including the PlGF isoforms), with and without TLR-agonists.

PlGF significantly increased TLR-mediated inflammatory cytokine production by syncytiotrophoblast cells in a time- and dose-dependent manner, and enhanced the magnitude of cytokine gene transcription. This PlGF/TLR effect was specific to PlGF-1, and PlGF-1 influenced the majority of but not all TLR-agonists.

We determined that PlGF influences TLR-pathway activation in syncytiotrophoblast cells, in a similar manner to its effect in mononuclear phagocytes. These results suggest that PlGF contributes to an exaggerated hyper-inflammatory state in diverse cells of the innate immune system and in syncytiotrophoblast cells, in response to infectious stimuli. PlGF may play a key role in the increased maternal and fetal susceptibility to infection-mediated inflammatory complications during pregnancy.