Epstein-Barr virus and its glycoprotein-350 upregulate IL-6 in human B-lymphocytes via CD21, involving activation of NF-kappa B and different signaling pathways

Epstein-Barr virus (EBV) is a ubiquitous and highly immunotropic gamma herp esvirus that infects more than 90% of humans worldwide. Its pathogenicity l eads to a number of diseases including tumors that result from EBV's abilit y to readily transform B-lymphocytes and, to a lesser extent, epithelial ce lls. EBV utilizes CD21/CR2 as its receptor on B cells to initiate the infec tion process. EBV binds to CR2 through its major envelope glycoprotein-350 (gp350) and is also a remarkable immunomodulating agent. We had previously shown that EBV is capable of modulating the synthesis of a number of cytoki nes. We now show that while both purified recombinant gp350 (rgp350) and EB V upregulate IL-6 mRNA synthesis in B cells, EBV-induced IL-6 gene activati on occurs for a significantly longer period of time (i.e. 12 hours for EBV as compared to 6 hours for rgp350). Moreover, the half-life of EBV-induced IL-6 mRNA was also significantly longer (10 hours) than that of mRNA induce d by rgp350 (about 6 hours). Both EBV and gp350 enhance the binding of the NF-kappaB transcription factor, as determined by band-shift and augment NF- kappaB-mediated activation of a CAT reporter plasmid. Furthermore, we demon strate that while the activation of IL-6 gene expression by gp350 is mediat ed primarily by the protein kinase C pathway, EBV can mediate its effects t hrough multiple signaling pathways. To our knowledge this is the first repo rt showing that the binding of a herpesvirus envelope glycoprotein to CR2 o n human B cells results in the activation of the NF-kappaB transcription fa ctor leading to the upregulation of IL-6 gene expression in these lymphocyt es. (C) 2001 Academic Press.