Epstein-Barr Virus and its glycoprotein-350 upregulate IL-6 in human B-lymphocytes via CD21, involving activation of NF-kappaB and different signaling pathways.
Epstein-Barr virus (EBV) is a ubiquitous and highly immunotropic gamma herpesvirus that infects more than 90 % of humans worldwide. Its pathogenicity leads to a number of diseases including tumors that result from EBV's ability to readily transform B-lymphocytes and, to a lesser extent, epithelial cells. EBV utilizes CD21/CR2 as its receptor on B cells to initiate the infection 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 cytokines. We now show that while both purified recombinant gp350 (rgp350) and EBV upregulate IL-6 mRNA synthesis in B cells, EBV-induced IL-6 gene activation 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 induced 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 demonstrate that while the activation of IL-6 gene expression by gp350 is mediated primarily by the protein kinase C pathway, EBV can mediate its effects through multiple signaling pathways. To our knowledge this is the first report showing that the binding of a herpesvirus envelope glycoprotein to CR2 on human B cells results in the activation of the NF-kappaB transcription factor leading to the upregulation of IL-6 gene expression in these lymphocytes.
D'Addario
M
M
Laboratory of Immunovirology, Department of Microbiology and Immunology and Pediatric Research Center, University of Montreal, and Ste. Justine Hospital, 3175 Côte Ste. Catherine, Montreal, Quebec H3T 1C5, Canada.
Libermann
T A
TA
Xu
J
J
Ahmad
A
A
Menezes
J
J
D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006207:Half-Life; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017464:Receptors, Complement 3d / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D014763:Viral Matrix Proteins / Q000378:metabolism*
D022782:CCAAT-Enhancer-Binding Protein-beta; D004791:Enzyme Inhibitors; C034059:GP 300-350, Epstein-Barr virus; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D017464:Receptors, Complement 3d; D011991:Receptors, Virus; D014763:Viral Matrix Proteins; D004247:DNA; D011493:Protein Kinase C