Binding of the Epstein-Barr virus major envelope glycoprotein gp350 results in the upregulation of the TNF-alpha gene expression in monocytic cells via NF-kappa B involving PKC, P13-K and tyrosine kinases

Epstein-Barr virus (EBV) is a human herpesvirus that interacts with various immunocompetent cells that carry the EBV receptor (CD21/CR2). EBV binds to CR2 through its major envelope glycoprotein 350 (gp350). Previously we had demonstrated that EBV and other human herpes-viruses are capable of modula ting cytokine synthesis through the deregulated expression of cytokine gene s interleukin-l (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha ( TNF-alpha), and interleukin-2 (IL-2). Here we show that, in contrast to inf ectious EBV, purified recombinant gp350 upregulates TNF-alpha gene expressi on in human monocyte/macrophages (M/M) as well as in a monocytoid cell line , U937. Our results also demonstrate that this increased expression is due to both enhanced transcription and stability of TNF-alpha mRNA in gp350-tre ated cells. The specificity of this effect is evidenced by the fact that pr e-incubation of cells with anti-CR2 monoclonal antibody OKB7, which blocks binding of gp350 to CR2, inhibits the above mentioned effects of gp350. Fur thermore, we demonstrate that activation of TNF-alpha by gp350 is mediated by NF-kappa B through signal transduction pathways involving PKC, PI3-K and tyrosine kinases. To our knowledge this is the first report describing the modulation of TNF-alpha gene expression by the EBV-gp350 molecule followin g its interaction with the viral receptor CR2 on cells of the monocytic lin eage. (C) 2000 Academic Press.