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

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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 β expression. Also, during the trophoblast‐maternal 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.