VIP modulates the pro‐inflammatory maternal response, inducing tolerance to trophoblast cells

Abstract

Background and purpose: Successful embryo implantation is followed by a local pro-inflammatory and Th1 response, subsequently controlled by a Th2 response. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects and promotes tolerogenic/Th2 responses while favouring embryonic development. We investigated the potential regulatory role of VIP on human trophoblast cells, maternal pro-inflammatory responses and trophoblast-maternal leukocyte interactions. Experimental approach: We tested VIP effects directly on a trophoblast cell line (Swan 71 cells) and after co-culture with maternal peripheral blood mononuclear cells (PBMCs) as models of the feto-maternal dialogue. We also co-cultured maternal and paternal PBMCs to test effects of endogenous VIP on maternal alloresponses. Key results: Swan 71 cells express VPAC1 receptors and VIP induced their proliferation and the expression of leukaemia inhibitor factor, a pro-implantatory marker. After interaction with trophoblast cells, VIP increased Foxp3, the proportion of CD4+CD25+Foxp3+ cells within maternal PBMCs and transforming growth factor b expression. Also, during the trophoblastmaternal PBMCs interaction, VIP reduced pro-inflammatory mediators [interleukin (IL)-6, monocyte chemoattractant protein 1, nitric oxide], while increasing IL-10. Trophoblast cells produced VIP which dose-dependently suppressed allomaternal responses, accompanied by reduced expression of the T cell transcription factor, T-bet. Conclusions and implications:Vasoactive intestinal peptide induced pro-implantatory markers and trophoblast cell proliferation, while controlling the initial pro-inflammatory response, by increasing maternal regulatory T cells and anti-inflammatory cytokines. As an autocrine regulatory peptide VIP might contribute to fetal survival through two mechanisms; a direct trophic effect on trophoblast cells and an immunomodulatory effect that favours tolerance to fetal antigens.

Potential immunomodulatory role of VIP in the implantation sites of prediabetic nonobese diabetic mice

“…The reduced expression of VIP at the sites of implantation of NOD mice confirms and extends the observations on the potential pro-implantatory role of VIP in the human maternal-fetal dialogue recently reported by means of an in vitro approach (Fraccaroli et al 2009). Further studies are needed to address the mechanisms underlying the potential role of VIP as a modulatory factor and the perspectives for its application to therapy of pregnancy failures.…”

“…We have recently reported on the expression of VIP and VIPR1 in a human trophoblast cell line (Fraccaroli et al 2009). By means of an experimental approach to the human fetal-maternal interface, we showed the participation of endogenous VIP in the fetalmaternal interaction with a pro-implantatory role by increasing the expression of Treg markers and LIF (Fraccaroli et al 2009). Other authors have reported on the ability of VIP to modulate hCG and progesterone in human trophoblast cultures (Marzioni et al 2005) and to be selectively concentrated in the uterine vasculature, where its levels have been reported to be 2.5-fold greater than in maternal blood (Ottesen et al 1982).…”

“…Moreover, a reduction in the levels of VIP could lead to growth retardation and microcephaly (Gressens et al 1994). We have recently reported on the expression of VIP and VIPR1 in a human trophoblast cell line (Fraccaroli et al 2009). By means of an experimental approach to the human fetal-maternal interface, we showed the participation of endogenous VIP in the fetalmaternal interaction with a pro-implantatory role by increasing the expression of Treg markers and LIF (Fraccaroli et al 2009).…”

A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system

“…VIP also has anti-inflammatory effects and, like progesterone, promotes a Th2 shift through the stimulation of IL10. DCs differentiated in the presence of VIP induce T regs , inhibiting allogeneic CD4 responses and increasing TGFB, suggesting a dual responsibility at the maternal-fetal interface (Fraccaroli et al 2009). …”

Contribution of Vasoactive Intestinal Peptide to Immune Homeostasis in Trophoblast-Maternal Leukocyte Interaction under LPS Stimulation

“…In this model, VIP increased the frequency of maternal CD4+CD25+Foxp3+ cells, TGF-β expression, and IL-10 secretion. Accordingly, it reduced proinflammatory mediators such as MCP-1, IL-6, and nitric oxide production [26]. …”