Immunoneutralization of endometrial monoclonal nonspecific suppressor factor beta (MNSFβ) inhibits mouse embryo implantation in vivo

Abstract

Successful embryo implantation and pregnancy in mammals depends on the establishment of immune tolerance between the maternal immune system and fetal cells. Monoclonal nonspecific suppressor factor beta (MNSFbeta), a cytokine produced by suppressor T cells in various tissues, possesses an antigen-nonspecific immune-suppressive function, and may be involved in the regulation of the uterine immune response during embryo implantation. In this study, anti-MNSFbeta IgG administered directly into the uterine lumen, significantly inhibited mouse embryo implantation in a dose-dependent manner in vivo, and this effect was reversed by co-administration of recombinant MNSFbeta. The effects of anti-MNSFbeta IgG on the gene pattern profiles in mouse uterine tissues were examined by cDNA microarray and several changes were confirmed by real-time PCR. Anti-MNSFbeta IgG caused up-regulation (> or = 2-fold) of 71 known genes and 17 unknown genes, and decreased expression (> or = 2-fold) of 74 known genes and 43 unknown genes, including several genes previously associated with embryo implantation or fetal development. Most of the known genes are involved in immune regulation, cell cycle/proliferation, cell differentiation/apoptosis, and lipid/glucose metabolism. These results demonstrate that MNSFbeta plays critical roles during the early pregnancy via multiple pathways.

Immunosuppressive Factor MNSFβRegulates Cytokine Secretion by Mouse Lymphocytes and Is Involved in Interactions between the Mouse Embryo and Endometrial CellsIn Vitro

“…This study demonstrates a stimulatory effect of MNSFβ on the secretion of IL-4 from mouse lymphocytes, as well as an inhibitory effect on their secretion of TNFα. Moreover, the results of the in vitro experiments using coculture model of mouse embryo and endometrial stromal cells to mimic embryo implantation in mice also showed that anti-MNSFβ antibody significantly inhibited embryo implantation (specifically hatching from the zona pellucida), consistent with and further defining the results of the in vivo experiments we previously reported [12].…”

“…The rabbit anti-mouse MNSFβ polyclonal antibody was prepared and its specificity previously demonstrated in our laboratory [12]. To detect the MNSFβ protein expression levels in transfected HCC-94 cells, 150 μL of protein lysis buffer (Beijing ComWin Biotech Co., Ltd., China) was added to each well.…”

“…Importantly, MNSFβ has been identified in association with implantation in mice: its expression was decreased at implantation sites but increased at interimplantation sites [11]. Furthermore, immunoneutralization of endometrial MNSFβ in vivo with a specific anti-MNSFβ antibody significantly inhibited mouse embryo implantation, potentially by disturbing fetomaternal immune tolerance, trophoblast invasion, or embryonic development [12], calling for the further investigation.…”

Autoimmune Activation toward Embryo Implantation is Rare in Immune-Privileged Human Endometrium

“…MNSF-β is an antigen nonspecific immune-suppressive cytokine produced by suppressor T cells, whose critical role during the embryo implantation has been shown in a murine model. 106 Blocking MNSF-β has even been proposed as a target for postcoital contraceptive drug. 107 A human ortholog of MNSF, human nonspecific suppressor factor, has been detected in ascitic fluid of patients with systemic lupus, 108 suggesting its role also in immune system regulation disorders leading to immune disease.…”

FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed)

“…Expression levels remain low as implantation advances (Nie et al, 2000). Administration of antisera to FAU into the mouse uterine lumen inhibits implantation in a dosedependent manner (Wang et al, 2007), suggesting an essential role for secreted products in implantation. Trophoblast-derived interferons have been shown to induce endometrial FAU expression in pigs (Chwetzoff and d'Andrea, 1997), also supporting an important role for FAU in early pregnancy.…”