Production of interferons in human placental trophoblast subpopulations and their possible roles in pregnancy

Abstract

The human cytotrophoblasts are the first fetal cells to arise during embryogenesis and are the progenitor cells to villous (noninvasive), syncytiotrophoblast (noninvasive), "intermediate" extravillous (invasive), and "anchoring" extravillous (invasive) trophoblast subpopulations. These trophoblast subpopulations were isolated from first- and third-trimester placentae and were stimulated with Sendai virus, granulocyte-macrophage colony-stimulating factors (GM-CSF), and platelet-derived growth factor (PDGF) to produce interferons (IFNs). GM-CSF and PDGF induced very low levels of IFN in first-trimester extravillous and villous trophoblast subpopulations. Highly proliferating and invasive intermediate extravillous trophoblast cultures produced five- to eightfold more IFNs than villous trophoblast cultures and two- to fivefold more IFN than the syncytiotrophoblast cultures when stimulated with Sendai virus. Syncytiotrophoblast cultures produced higher levels of IFNs (up to twofold) than villous trophoblast cultures when stimulated with the same virus. Pretreatment of first-trimester extravillous and villous trophoblast cultures with GM-CSF and PDGF followed by infection with Sendai virus resulted in greater IFN production than when the cultures were stimulated with virus alone. The levels of IFN produced were dependent on the type of trophoblast, the type of inducer, and the stage of differentiation of the trophoblasts. The purified trophoblast IFNs have potent antiviral activities when assayed on human amniotic WISH cells, and they inhibited proliferation of normal trophoblasts and trophoblast-derived malignant cells in vitro without any toxicity. Furthermore, the trophoblast IFNs activated NK cell activity and suppressed mitogen-stimulated lymphocyte proliferation at concentrations of between 10 and 1,000 IU/ml. The possible functions of the trophoblast IFNs during pregnancy are discussed with respect to human placental and fetal protection and development.

Interferons and Uterine Receptivity

“…Type I and type II IFNs appear to be produced by human placenta and decidual cells. 26,27,[88][89][90] Aboagye-Mathiesen et al 26,90 reported that human extravillous and villous trophoblast from the first and third trimesters of human pregnancy produce IFNA and IFNB when cultured in the presence of granulocyte-monocyte colony-stimulating factor and platelet-derived growth factor followed by infection with Sendai virus, whereas trophoblast produced IFNB in response to doublestranded RNA or both IFNA and IFNB in response to Sendai and Newcastle disease viruses. These researchers speculated that these IFNs might (1) regulate proliferation of trophoblast or other cells in the uterus; (2) exert immunosuppressive effects by suppressing mitogen-induced proliferation of T-and B-cells; (3) protect the conceptus from viral infections; (4) regulate cellular differentiation and expression of cell surface antigens; (5) stimulate expression of e-globin, a component of embryonic hemoglobin; and (6) suppress expression of proto-oncogenes such as EGFR, c-erB2, and c-fms to affect trophoblast growth and differentiation.…”

“…92 Given that ISGs are highly upregulated in human endometrial stromal cells in response to human trophoblast conditioned culture medium, rigorous studies are needed to identify temporal and cell-specific expression of antiviral molecules by human placentae. 72 IFNA protein present in syncytiotrophoblast 93 is released from explant cultures of human trophoblast 88 and, of particular importance, IFNA may stimulate transcription of the CGB gene without effects on cell proliferation. 94 However, this effect of IFNA on CGB production by bladder tumor cell lines has not been confirmed using trophectoderm cells.…”

The effects of maternal inflammation on neuronal development: possible mechanisms

“…Thus, proper levels of interferons may be essential for fetal protection. Cytotrophoblasts and their progeny, syncytiotrophoblasts and invasive trophoblasts, can be stimulated in culture with Sendai virus, platelet‐derived growth factor (PDGF) or granulocyte/monocyte colony‐stimulating factor (GM‐CSF, a normal constituent of the placenta (Crainie et al, 1990; Jokhi et al, 1994; Kanzaki et al, 1991; Loke et al, 1992)) to produce interferons (Aboagye‐Mathiesen et al, 1994; Aboagye‐Mathiesen et al, 1995; Imakawa et al, 1997; Toth et al, 1990b; Toth et al, 1990a). While the mechanism remains obscure, it is noteworthy that maternal treatment with IFNγ or GM‐CSF prevents neural tube defects caused by valproic acid‐induced inflammation (Hrubec et al, 2006).…”

The Role of Subpopulations of Cd8+ T Lymphocytes in the Development of Pregnancy

“…Expression of PD-1L with trophoblast is stimulated by EGF and IFNγ [48]. It is likely that increased production of IFNγ trophoblast in early pregnancy [3,4] and its autocrine effect may be one of the mechanisms of survival of a semi-allogenic foetus as a result of the interaction of PD-1 on T lymphocytes and PD-1L on the trophoblast. From the first to the second trimester, the expression of PD-1L in the placenta is increased, the regulation of expression is probably carried out depending on oxygenation (insufficient oxygenation in the uteroplacental blood flow zone causes a decrease in expression of PD-1L) [49].…”