Epstein-Barr virus (EBV) is a highly immunotropic human herpesvirus with oncogenic potential and is involved in numerous pathologies. EBV utilizes its major envelope glycoprotein gp350 to bind to its receptor CR2/CD21 on target cells for initiating the infection. We have previously shown that EBV is able to modulate transcription and translation of a number of cytokine genes via its gp350-mediated binding to this receptor. However, the effects of the binding of purified gp350 to CR2/CD21 on plastic-adherent monocyte-macrophages (AMM) have not been investigated. These cells are a rich source of potent proinflammatory and immune-modulating cytokines, and express low levels of CR2/CD21. We show here for the first time that recombinant gp350 (rgp350) causes production of the potent proinflammatory cytokine IL-1beta in human AMM. Surprisingly, rgp350 is comparable in this capacity to the phorbol ester 12-0-tetradecanoylphorbol 13-acetate. This induction of IL-1beta production was accompanied by increased steady-state levels of its mRNA in gp350-treated AMM, and was dependent on the specific binding of rgp350 to the EBV receptor CR2/CD21. We also show that the signaling pathways resulting in the induction of IL-1beta synthesis by rgp350 required protein kinase C and phosphatidylinositol 3,4,5 triphosphate kinase activities and occurred via activation of the NF-kappaB family of transcription factors.-D'Addario, M., Ahmad, A., Xu, J. W., Menezes, J. Epstein-Barr virus envelope glycoprotein gp350 induces NF-kappaB activation and IL-1beta synthesis in human monocytes-macrophages involving PKC and PI3-K.