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: Chien-Hsun Lee, Tzu-Hao Yeh, Hsiao-Ching Lai, Shih-Yi Wu, Ih-Jen Su, Kenzo Takada, Yao Chang
• Journal: Journal of virology (J Virol) Vol. 85 Issue 14 Pg. 7333-42 (Jul 2011) ISSN: 1098-5514 [Electronic] United States
• PMID: 21543473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• DNA Primers
• Interleukin-10
• Granulocyte-Macrophage Colony-Stimulating Factor
• Dinoprostone

Topics

• Base Sequence
• Cell Line, Tumor
• Culture Media, Conditioned
• DNA Primers
• Dinoprostone (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Herpesvirus 4, Human (physiology)
• Humans
• Interleukin-10 (biosynthesis)
• Nasopharyngeal Neoplasms (metabolism, pathology)
• Polymerase Chain Reaction