Analysis of Interleukin-27 (EBI3/p28) Expression in Epstein-Barr Virus- and Human T-Cell Leukemia Virus Type 1-Associated Lymphomas

Abstract

Interleukin (IL)-27 is a novel heterodimeric cytokine of the IL-12 family that is composed of two subunits, Epstein-Barr virus (EBV)-induced gene 3 (EBI3) and p28. EBI3 is expressed at high levels in EBV-transformed B-cell lines and is induced in vitro by the EBV oncogene LMP1 in a nuclear factor (NF)-kappaB-dependent manner. We show here that EBI3 expression is up-regulated in human T-cell leukemia virus type 1 (HTLV-1)-infected cell lines and IL-2-dependent leukemic cells from adult T-cell leukemia/lymphoma (ATL) patients, compared to normal activated T cells. EBI3 expression was decreased in HTLV-1-transformed cells after treatment with the NF-kappaB inhibitor BAY11-7082 and was induced in Jurkat cells by expression of HTLV-1 wild-type Tax oncoprotein, but not by the Tax mutant M22, which is defective for NF-kappaB activation. In situ analysis of EBI3 and p28 expression in Hodgkin's lymphomas (HLs), in various EBV-associated lymphoproliferative disorders (LPDs) (including post-transplant LPDs and nasal-type NK/T-cell lymphomas), and in ATL showed that EBI3 was expressed by neoplastic cells in all cases of HL and of LMP1-positive EBV-associated LPD, at variable levels in ATL cases, but rarely in control T-cell lymphomas. In contrast, in all lymphomas tested, no or few tumoral cells expressed p28. Consistent with these data, no significant p28 or IL-27 expression was detected in HL-derived cell lines, or in EBV- or HTLV-1-transformed cell lines. This selective overexpression of EBI3 by transformed cells suggests that EBI3 may play a role, independently from its association to p28, in regulating anti-viral or anti-tumoral immune responses.

Human CD4+CD25+Foxp3+ Regulatory T Cells Do Not Constitutively Express IL-35

“…In a previous study, we showed that low levels of EBI3 could be induced in human T cells upon in vitro stimulation with PHA and IL-2 (14). Therefore, to further analyze the expression of EBI3 in human T cells, whole CD4 ϩ T cells or subsets of naive or memory CD4 ϩ T, Treg, and Teff cells were stimulated for 2 days with beads coated with anti-CD3 and anti-CD28 Abs (a more physiological stimulus than PHA) in the absence or presence of IL-2, and cell lysates were analyzed for EBI3 expression by immunoblotting (Fig.…”

Differential Effects of IL-27 on Human B Cell Subsets

“…In mouse or human primary cultures in vitro, IL-27 was found to be primarily expressed by activated monocytes and monocyte-derived dendritic cells, whereas in human tissues EBI3 and p28 coexpression was predominantly observed in macrophages or macrophage-derived cells and in endothelial cells (2)(3)(4). IL-27 receptor complex comprises two ␤-chains, IL-27R (also called WSX-1 or TCCR) and gp130 (2,5).…”

Identification of polymorphisms in human interleukin-27 and their association with asthma in a Korean population

“…In comparison with wild-type mice, WSX-1 (-/-) mice manifest significantly increased levels of airway immune response and serum IgE with infiltration of the pulmonary eosinophil, indicating that IL-27 and WSX-1 have a function in the down-regulation of airway hyper-reactivity and lung inflammation during the development of allergic asthma (Miyazaki et al 2005). The dissociated expression of EBI3 and p28 in transformed cells suggests that EBI3 may play a role -independent of its association with p28 -in the regulation of anti-viral and anti-tumoral responses (Larousserie et al 2005).…”