Abstract
Trophoblast cells migrate and invade the decidual stroma in a tightly regulated process to maintain immune homeostasis at the maternal-placental interface during the first weeks of pregnancy. Locally synthesized factors modulate trophoblast cell function and their interaction with maternal leukocytes to promote the silent clearance of apoptotic cells. The vasoactive intestinal peptide (VIP) is a pleiotropic polypeptide with trophic and anti-inflammatory effects in murine pregnancy models. We explored the effect of VIP on two human first trimester trophoblast cell lines, particularly on their migration, invasiveness and interaction with phagocytic cells, and the signalling and regulatory pathways involved. We found that VIP enhanced trophoblast cell migration and invasion through the activation of high affinity VPAC receptors and PKA-CRE signalling pathways. VIP knocked-down trophoblast cells showed reduced migration in basal and leukemic inhibitor factor (LIF)-elicited conditions. In parallel, VIP-silenced trophoblast cells failed to induce the phagocytosis of apoptotic bodies and the expression of immunosuppressant markers by human monocytes. Our results suggest that VIP-mediated autocrine pathways regulate trophoblast cell function and contribute to immune homeostasis maintenance at placentation and may provide new clues for therapeutic intervention in pregnancies complicated by defective deep placentation.
Highlights
Trophoblast cells migrate and invade the decidual stroma in a tightly regulated process to maintain immune homeostasis at the maternal-placental interface during the first weeks of pregnancy
Trophoblast cells transfected with cAMP response element sites (CRE)-Luc plasmid presented a diminished CRE activation when they were cultured in basal conditions in the presence of a vasoactive intestinal peptide (VIP) antagonist suggesting an autocrine activation of VIP signalling (Fig. 1c)
Since VIP is a pleiotropic polypeptide with trophic and immunomodulatory effects in different pregnancy models, we investigated VIP autocrine pathways that regulate trophoblast function through high affinity VPAC1 and VPAC2 receptors and their interaction with phagocytic cells by means of loss and gain of function assays performed in two first trimester trophoblast cell lines
Summary
Trophoblast cells migrate and invade the decidual stroma in a tightly regulated process to maintain immune homeostasis at the maternal-placental interface during the first weeks of pregnancy. We explored the effect of VIP on two human first trimester trophoblast cell lines, on their migration, invasiveness and interaction with phagocytic cells, and the signalling and regulatory pathways involved. We found that VIP enhanced trophoblast cell migration and invasion through the activation of high affinity VPAC receptors and PKA-CRE signalling pathways. VIP and VPAC receptors are expressed in the human first trimester trophoblast cell line Swan 7122,23. There are no reports on VIP effects on migration and invasion capacities of human first trimester trophoblast cells, the signalling cascades and potential autocrine regulatory pathways involved. Our results demonstrate that VIP synthesized by human first trimester trophoblast cell lines Swan 71 and HTR8 increases cell migration and invasiveness involving PKA/CRE signalling and autocrine pathways. VIP knocked down trophoblast cells failed to promote the phagocytosis of apoptotic cells by human monocytes and to induce anti-inflammatory markers
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