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

Immunopharmacology Laboratory, Department of Biological Chemistry, School of Exact and Biological Sciences, University of Buenos Aires, CONICET, Ciudad Universitaria, Pab. II, 4th Floor, 1428 Buenos Aires, Argentina¹ Laboratory of Physiopathology of Pregnancy and Labor, School of Medicine, Center for Pharmacological and Botanical Studies (CEFYBO), University of Buenos Aires, CONICET, Paraguay 2155, 1121 Buenos Aires, Argentina

Correspondence should be addressed to C Pérez Leirós; Email: cpleiros{at}qb.fcen.uba.ar

Among several factors known to modulate embryo implantation and survival, uterine quiescence and neovascularization, maternal immunotolerance through the Th1/Th2 cytokine balance towards a Th2 profile, local regulatory T-cell (Treg) activation, and high levels of progesterone were assigned a prominent role. Vasoactive intestinal peptide (VIP) is a neuroimmunopeptide that has anti-inflammatory effects, promotes Th2 cytokines and CD4⁺CD25⁺FOXP3⁺ 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 implantation sites of normal and pregnant prediabetic nonobese diabetic (NOD) females, a mouse strain that spontaneously develops an autoimmune exocrinopathy similar to Sjögren's syndrome. Our results indicate a reduction in litter size from the third parturition onwards in the NOD female lifespan with increased resorption rates. Progesterone systemic levels were significantly decreased in pregnant NOD mice compared with BALB/c mice, although the allogeneic response to progesterone by spleen cells was not impaired. VIP receptors, Vipr1 and Vipr2 (Vpac1 and Vpac2), were expressed at the implantation sites and VIP induced leukemia inhibitory factor (LIF) and Treg marker expression in both strains; however, a reduced Vip expression was found in NOD implantation sites. We conclude that the reduced birth rate at 16-week-old NOD mice with a Th1 systemic cytokine profile involves resorption processes with a lower expression of VIP at the sites of implantation, which acts as a local inducer of pro-implantatory LIF and Treg activation.