Expression of Epstein-Barrvirus-induced gene 3, an interleukin-12 p40-related molecule, throughout human pregnancy - Involvement of syncytiotrophoblasts and extravillous trophoblasts

in human pregnancy, trophoblasts are the only cells of fetal origin in dire ct contact with the maternal immune system: syncytiotrophoblasts are in con tact with maternal blood, whereas extravillous trophoblasts are in contact with numerous maternal uterine natural killer (NK) cells. Therefore, tropho blasts are thought to play a key role in maternal tolerance to the semiallo geneic fetus, in part through cytokine production and NK cell interaction. Epstein-Barr virus-induced gene 3 (EBI3) encodes a soluble hematopoietin re ceptor related to the p40 subunit of interleukin-12. Previous studies indic ated that EBI3 is expressed in the spleen and tonsils, and at high levels i n full-term placenta. To investigate further EBI3 expression throughout hum an pregnancy, we generated monoclonal antibodies specific for EBI3 and deve loped an EBI3 enzyme-linked immunosorbent assay. Immunohistochemical experi ments with EBI3 monoclonal antibody on first-, second-, and third-trimester placental tissues demonstrated that EBI3 was expressed throughout pregnanc y by syncytiotrophoblasts; and extravillous trophoblasts (cytotrophoblast c ell columns, interstitial trophoblasts, multinucleated giant cells, and tro phoblasts of the chorion laeve). EBI3 expression was also induced during in vitro differentiation of trophoblast cell lines. in addition, large amount s of secreted EB13 were detected in explant cultures from first-trimester a nd term placentae. Consistent with these data, EBI3 levels were strongly up -regulated in sera from pregnant women and gradually increased with gestati onal age. These data, together with the finding that EBI3 peptide is presen ted by HILA-G, suggest that EBI3 is an important immunomodulator in the fet al-maternal relationship, possibly involved in NK cell regulation.