In fact, the immunomodulatory effects of VIP were prevented by a VIP antagonist, indicating the endogenous JQ1 in vitro VIP contribution. Therefore, VIP might act as a tolerogenic factor modulating
the Th1/Treg effector responses and the production of pro/anti-inflammatory mediators promoting an overall balance that favours tolerance towards trophoblast antigens. The role of VIP in the maintenance of immune tolerance by expansion of the Treg population has been demonstrated [32, 33]. In fact, VIP was able to modulate the Treg subpopulation in several acute and chronic inflammatory processes [37-41]. Previously, in line with this, we have demonstrated Treg cell modulation by VIP through the up-regulation of FoxP3 and TGF-β in pancreas of diabetic NOD mice, which may lead to the restoration of tolerance to pancreatic autoantigens [17]. VIP expression was detected only in selleck screening library decidua and trophoblast cells, with a peak at day 8 of gestation in the murine model [19].
However, when extra-embryo tissues were separated from the embryo, the main source of VIP production was from maternal lymphocytes. This transient VIP expression correlates with the critical period of VIP effects as an embryo growth regulator and a neural growth factor [19, 42, 43]. Consistent with a strict regulation of the immune response during pregnancy, thrombotic/inflammatory processes are often observed at the maternal–fetal interface as the final pathological assault of pregnancy losses in many
cases, including those of unexplained aetiologies. Tissue damage and embryo resorption is associated Janus kinase (JAK) with the failure of several immunological mechanisms, such as an exacerbated inflammatory/Th1 response, ultimately responsible for cytotoxic natural killer activation and reflected by elevated leucocyte infiltration [9, 44] or limited maternal repertoire of killer inhibitory receptors and lack of fetal human leucocyte antigen Cw (HLA-Cw) molecules on trophoblast cells [30], among others [6, 8]. In this study, we evaluated the role of immunomodulatory VIP in the trophoblast–maternal cell interaction under normal and pathological conditions, using maternal PBMCs from fertile or RSA women. Our results showed clearly that RSA PBMCs displayed an exacerbated proinflammatory and Th1 immune response after interaction with trophoblast cells, reflected by an increase in T-bet expression level and nitrite production. Conversely, we observed a significant decrease in the frequency of Treg cells in these co-cultures with lower levels of TGF-β and IL-10 secretion.