PRODUCTION OF INTERFERONS IN HUMAN PLACENTAL TROPHOBLAST SUBPOPULATIONS AND THEIR POSSIBLE ROLES IN PREGNANCY

The human cytotrophoblasts are the first fetal cells to arise during e mbryogenesis and are the progenitor cells to villous (noninvasive), sy ncytiotrophoblast (noninvasive), ''intermediate'' extravillous (invasi ve), and ''anchoring'' extravillous (invasive) trophoblast subpopulati ons. These trophoblast subpopulations were isolated from first- and th ird-trimester placentae and were stimulated with Sendai virus, granulo cyte-macrophage colony-stimulating factors (GM-CSF), and platelet-deri ved growth factor (PDGF) to produce interferons (IFNs). GM-CSF and PDG F induced very low levels of IFN in first-trimester extravillous troph oblast cultures produced five- to eightfold more IFNs than villous tro phoblast cultures and two- to fivefold more IFN than the syncytiotroph oblast 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 g reater IFN production than when the cultures were stimulated with viru s alone. The levels of IFN produced were dependent on the type of trop hoblast, the type of inducer, and the stage of differentiation of the trophoblasts. The purified trophoblast IFNs have potent antiviral acti vities when assayed on human amniotic WISH cells, and they inhibited p roliferation 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 lymphocy te proliferation at concentrations of between 10 and 1,000 IU/ml. The possible functions of the trophoblast IFNs during pregnancy are discus sed with respect to human placental and fetal protection and developme nt.