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

VALERIA ROCA; MARIO CALAFAT; LUCIANA LAROCCA; ROSANNA RAMHORST; MARIANA FARINA; ANA FRANCHI; CLAUDIA PEREZ LEIROS

REPRODUCTION

Año: 2009 p. 733 - 742

1470-1626

Among several factors known to modulate embryo implantation and survival, uterine quiescence and neovascularization, maternalimmunotolerance through the Th1/Th2 cytokine balance towards a Th2 profile, local regulatory T-cell (Treg) activation, and high levelsof progesterone were assigned a prominent role. Vasoactive intestinal peptide (VIP) is a neuroimmunopeptide that has anti-inflammatoryeffects, promotes Th2 cytokines and CD4CCD25CFOXP3C Treg activation, and stimulates exocrine secretion, smooth muscle relaxation,and vasodilatation favoring uterus quiescence. The goal of the present work was to explore the participation of VIP in the implantationsites of normal and pregnant prediabetic nonobese diabetic (NOD) females, a mouse strain that spontaneously develops an autoimmuneexocrinopathy similar to Sjo¨gren’s syndrome. Our results indicate a reduction in litter size from the third parturition onwards in the NODfemale lifespan with increased resorption rates. Progesterone systemic levels were significantly decreased in pregnant NOD micecompared with BALB/c mice, although the allogeneic response to progesterone by spleen cells was not impaired. VIP receptors, Vipr1and Vipr2 (Vpac1 and Vpac2), were expressed at the implantation sites and VIP induced leukemia inhibitory factor (LIF) and Treg markerexpression in both strains; however, a reduced Vip expression was found in NOD implantation sites.We conclude that the reduced birthrate at 16-week-old NOD mice with a Th1 systemic cytokine profile involves resorption processes with a lower expression of VIP at thesites of implantation, which acts as a local inducer of pro-implantatory LIF and Treg activation.