title: Potential immunomodulatory role of VIP in the implantation sites of prediabetic nonobese diabetic mice.
abstract: 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.
authors.affiliation: Immunopharmacology Laboratory, Department of Biological Chemistry, School of Exact and Biological Sciences, University of Buenos Aires, Argentina.
authors.forename: Valeria
authors.initials: V
authors.lastname: Roca
authors.forename: Mario
authors.initials: M
authors.lastname: Calafat
authors.forename: Luciana
authors.initials: L
authors.lastname: Larocca
authors.forename: Rosanna
authors.initials: R
authors.lastname: Ramhorst
authors.forename: Mariana
authors.initials: M
authors.lastname: Farina
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Franchi
authors.forename: Claudia Pérez
authors.initials: CP
authors.lastname: Leirós
mesh_terms: D000818:Animals; D016640:Diabetes, Gestational / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010064:Embryo Implantation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D020964:Embryo Loss / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D007155:Immunologic Factors / Q000494:pharmacology / Q000502:physiology*; D008098:Litter Size; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011236:Prediabetic State / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: D007155:Immunologic Factors; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495507:Vipr1 protein, mouse; C495510:Vipr2 protein, mouse; D014660:Vasoactive Intestinal Peptide