Expression of interleukin-27 by human trophoblast cells.

Cytokines produced at the fetal-maternal interface play a key role in regulating maternal tolerance to the fetus and successful pregnancy. Previously, we showed that EBV-induced gene 3 (EBI3), an interleukin (IL)-12 p40 homologue, was expressed at very high levels by syncytiotrophoblasts and extravillous trophoblasts throughout human pregnancy. EBI3 was recently shown to associate with a novel ligand, p28, to form a new heterodimeric cytokine with important immunoregulatory functions, IL-27. In this study, we investigated whether EBI3 expression by trophoblast cells is associated with that of p28 to form IL-27. We found that genes encoding IL-27 (EBI3 and p28) and its receptor (IL-27R and gp130) were expressed in the placenta at various stages of pregnancy. Co-immunoprecipitation experiments performed from placental lysates, and ELISA of culture supernatants from placental explants, showed that IL-27 heterodimer was produced and released from placental cells. In situ studies of placentae of first, second and third trimester of pregnancy, and of choriocarcinomas, demonstrated that syncytiotrophoblast cells co-expressed EBI3 and p28. Similarly, extravillous trophoblast cells invading the decidua were found to co-express both subunits of IL-27. These data suggest that IL-27 may be part of the cytokine network regulating local immune responses and angiogenesis during human pregnancy.

Variable expression of Epstein-Barr virus-induced gene 3 during normal B-cell differentiation and among B-cell lymphomas.

Epstein-Barr virus (EBV)-induced gene 3 (EBI3) is expressed by tumour cells in several EBV-associated malignancies. EBI3 was recently found to associate with a novel peptide, p28, to form a new heterodimeric cytokine, called interleukin-27. In this study, we investigated EBI3 and p28 expression in normal human B lymphocytes and in non-EBV-associated B-cell lymphomas. Low levels of EBI3 were detected in purified tonsillar B cells and expression was upregulated upon anti-CD40 or anti-micro stimulation via NF-kappaB activation. In non-neoplastic tissues, EBI3 expression by lymphocytes was largely restricted to a subset of germinal centre (GC) B cells located at the margin of the light zone, in close contact with CD3+ T lymphocytes. Over 50% of EBI3+ GC B cells were engaged in cell proliferation as assessed by Ki67 expression, and 10-30% expressed MUM1, an early marker of plasma cell differentiation expressed by late centrocytes. Many EBI3+ GC B cells had downregulated bcl-6 expression, which further suggests that these cells correspond to late CD40-activated centrocytes. Immunohistochemical analysis of 64 B-cell lymphomas showed that the highest EBI3 levels were detected in follicular lymphomas and in diffuse large B-cell lymphomas of both GC B-cell-like or non-GC B-cell-like types. No or rare p28 expression was detected in normal or tumour B cells. This constitutive expression of EBI3 by neoplastic B cells may be involved in lymphomagenesis, and may be a useful marker for lymphoma diagnosis.