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Tumor associated glycoprotein-72 (TAG-72) binds to the mannose receptor on decidual macrophages and enables them to induce Interleukin-4 production in naive T cells

INTRODUCTION: The interaction of the Carbohydrate Recognition Domain (CRD) of the mannose receptor (MR) with glycoprotein(s) at the maternal-fetal interface could promote an anti-inflammatory and tolerogenic program including Th2 cytokine production indispensable for maintaining of pregnancy. Tumor Associated Glycoprotein-72 (TAG-72), although the marker of various human malignancies, is produced throughout normal human female genital tract on a progesterone dependent manner and according to high glycosilation level could be possible natural ligand for the MR. The aim of our study was to analyze: the expression and distribution of the MR in the first trimester pregnancy decidua and term placenta, as well as possible binding properties of TAG-72 to the CRD of the MR and the effect of TAG-72 on the endocytic activity and tolerogenic program in MR positive cells. MATERIAL AND METHODS: The MR and CD14 or CD83 expression were analyzed by double labelling with mouse anti-human MR monoclonal antibody (MoAb) and anti-CD14 or anti-CD83 MoAb in frozen tissue sections of the first trimester deciduas and term placentas (using DAKO Envision Doublestain System) and/or mononuclear cell suspensions obtained by enzymatic digestion of the first trimester decidual tissue (two color immunofluorescency). Endocytic activity was measured by FITC-Dextran uptake in macrophages from 18 hr-cultured or freshly isolated decidual mononuclear cell suspensions, untreated or treated with increasing concentrations of mannan (the ligand for CRD) or TAG-72. The induction of interleukin-4 protein synthesis was analyzed by double-color immmunofluorescency in permeabilized cord blood T cells after 3 day culture with magnetically separated (Vario MACS Column) decidual CD14 positive cells untreated or pre-treated with TAG-72 (200 U/ml), LPS (10 ng/ml) or TAG-72 and LPS. RESULTS: Contrary to disseminated distribution of the MR positive cells in term placenta, in the first trimester pregnancy decidua the MR positive cells were distributed mostly around the glands. These cells follow tissue distribution of CD14 positive macrophages and approximately half of the CD14 positive cells were MR positive at the same time. Additionally, MR was expressed on endothelial cells inside the villa vessels. In the isolated cell suspensions, decidual macrophages were also predominant cell population, which when freshly isolated, internalized FITC-Dextran more efficiently compared to 18-hour cultured and mannan or TAG-72 pre-treated freshly isolated cells. Decidual CD14 positive cells pre-treated with TAG-72 or TAG-72 and LPS were capable to induce IL-4 protein synthesis in cord blood naive T cells. CONCLUSION: The mannose receptor positive macrophages, surrounding early decidual glands are capable to bind and internalize decidual secretory phase mucin TAG-72 that enables them to induce interleukin-4 cytokine production in naive T cells.

Mannose receptor; Decidual macrophages; Interleukin 4; T cells; TAG-72; Th2 cytokineMannose receptor; Decidual macrophages; Interleukin 4; T cells; TAG-72; Th2 cytokine

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