Cytokine mediated induction of the major Epstein-Barr virus (EBV)-encoded transforming protein, LMP-1

Abstract

In the in vitro infected B-cells six EBV-encoded nuclear antigens (EBNA-1-6) and three latent membrane proteins (LMP-1, -2A, -2B) are expressed (type III latency). In addition, other restricted forms of latency occur in the EBV-carrying malignancies. In Burkitt lymphoma (BL) only EBNA-1 is expressed (type I), while in Hodgkin lymphoma (HL), T-, and NK-lymphoma, and nasopharyngeal carcinoma EBNA-1 and LMPs are expressed (type II). B-cells with these three expression patterns have been detected in healthy virus carriers. While in type III latency two viral transcriptional activators, EBNA-2 and -5, are responsible for LMP-1 expression, the mechanism that controls the expression of LMP-1 in type II latent cells is not known. In order to study the interaction of EBV- and HL-derived cells, we studied the in vitro EBV-converted subline of the KMH2 cells that express only EBNA-1 and LMP-2A. Interestingly, exposure of the KMH2-EBV cells to CD40-ligand and IL-4 induced LMP-1 expression, in the absence of EBNA-2. In BL cell lines lacking EBNA-2 another cytokine, IL-10, could induce LMP-1 expression. IL-10 induced LMP-1 also in tonsillar B-cells infected with the EBNA-2-deleted virus strain P3HR-1. Our results show that cytokines are responsible for the expression of LMP-1 in type II latent B-cells. These signals are available in the germinal center environment and in the granulation tissue of HLs. Based on these results we propose that LMP-1 expression is induced by extracellular signals and is not a constitutive characteristic of the EBV-carrying type II B-cells. Cytokine mediated induction of LMP-1 may also explain the heterogeneous expression of this viral gene seen in normal and malignant cells.