title: Epstein-Barr virus Zta-induced immunomodulators from nasopharyngeal carcinoma cells upregulate interleukin-10 production from monocytes.
abstract: During lytic infection with Epstein-Barr virus (EBV), several viral lytic proteins function to evade immune recognition or to actively suppress immune cells. An EBV lytic transactivator, Zta, induces an immunosuppressive cytokine interleukin 10 (IL-10) in B cells, but whether it regulates IL-10 in the context of epithelial cells is unclear. In this study, we tested nasopharyngeal carcinoma (NPC) cell lines and found that Zta did not induce IL-10 in these epithelial cells. Interestingly, the conditioned medium of Zta-expressing NPC cells enhanced IL-10 production from monocytes. We further revealed that the IL-10-inducing effect involved at least two immunomodulators that were upregulated by Zta and secreted from NPC cells: granulocyte-macrophage colony-stimulating factor (GM-CSF) and prostaglandin E(2) (PGE(2)). Zta was recruited to and activated the GM-CSF promoter, thus upregulating GM-CSF expression. Zta also activated the promoter of cyclooxygenase-2 (COX-2), and Zta-induced COX-2 increased downstream PGE(2) production. Cotreatment with GM-CSF and PGE(2) synergistically induced IL-10 production from monocytes. The IL-10-inducing effect of the Zta-conditioned medium was reduced when GM-CSF or the COX-2/PGE(2) pathway was blocked. The conditioned medium of NPC cells with EBV lytic infection showed a similar increase of GM-CSF and PGE(2) levels as well as the IL-10-inducing effect on monocytes, and knockdown of Zta abolished all the effects. Therefore, through Zta-induced immunomodulators, EBV lytic infection in NPC cells can direct bystander monocytes to produce IL-10, which may be a novel way of EBV to promote local immunosuppression.
authors.affiliation: Division of Infectious Diseases, National Health Research Institutes, Tainan 704, Taiwan.
authors.forename: Chien-Hsun
authors.initials: CH
authors.lastname: Lee
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Yeh
authors.forename: Hsiao-Ching
authors.initials: HC
authors.lastname: Lai
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Wu
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takada
authors.forename: Yao
authors.initials: Y
authors.lastname: Chang
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D017931:DNA Primers; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction
chemical_list: D017077:Culture Media, Conditioned; D017931:DNA Primers; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015232:Dinoprostone