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

INTRODUCTION

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.

METHODS

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

RESULTS

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.

DISCUSSION: 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.