EB病毒再活化進入溶裂期和衍生自上皮細胞的鼻咽癌高度相關。在鼻咽癌組織中會有大量白血球浸潤，並在此部位存有強烈的免疫抑制的情況。EB病毒的溶裂期蛋白質Zta是一個強效的轉錄活化子，可以在鼻咽癌細胞中上調許多細胞激素及趨化因子的表現，經由這些分泌的因子可能進而影響腫瘤周邊浸潤的免疫細胞。本篇研究利用抗體陣列分析發現，表現Zta的鼻咽癌細胞所收取的培養上清液可以促進單核球細胞株以及其分化的巨噬細胞產生介白素-10(IL-10)。我們進一步找出了兩個Zta所誘發的免疫調節物質參與了誘導單核球及巨噬細胞分泌IL-10：顆粒單核球群落刺激生長因子(GM-CSF)及前列腺素E2(PGE2)。以重組GM-CSF和PGE2刺激，可協同誘導單核球分泌IL-10；而PGE2單獨即可誘導巨噬細胞分泌IL-10。活化PGE2受體EP2/4的促效劑也可達到誘導骨髓系細胞分泌IL-10的效用。Zta能轉錄活化鼻咽癌細胞GM-CSF啟動子的-161至-5區域進而促使GM-CSF分泌；另一方面，利用環氧化酶-2(COX-2)之siRNA以及其抑制劑，證實Zta經由誘導COX-2蛋白質表現進而增加其下游PGE2的分泌。類似的結果也可以於EB病毒溶裂期感染的鼻咽癌細胞被觀察到：EB病毒的再活化可誘發鼻咽癌細胞表現GM-CSF、COX-2和PGE2，並且促進骨髓系細胞分泌IL-10。利用Zta siRNA阻斷EB病毒溶裂期進行可抑制免疫調節物質的增加及IL-10的分泌。我們的研究結果暗示，EB病毒感染的鼻咽癌細胞可能利用Zta所誘發的免疫調節物質指揮浸潤在周圍的骨髓系免疫細胞分泌抑制性細胞激素IL-10，進而建立一個偏向逃避抗腫瘤以及抗病毒免疫反應的腫瘤微環境。

Epstein-Barr virus (EBV) reactivation into the lytic cycle has been highly associated with nasopharyngeal carcinoma (NPC), an epithelial malignancy with intensive leukocyte infiltration and local immunosuppression. The EBV lytic transactivator Zta can upregulate many cytokines and chemokines in NPC cells, so it may affect bystander immune cells through these secreted factors. In this study, using antibody array analysis, we reveal that culture supernatants of Zta-expressing NPC cells enhance production of interleukin-10(IL-10) from human monocytic cell lines and macrophages derived from them. We further propose that two Zta-induced immunomodulators may be involved in the IL-10 induction: granulocyte-macrophage colony-stimulating factor (GM-CSF) and prostaglandin E2 (PGE2). Recombinant human GM-CSF and PGE2 synergistically promote IL-10 secretion from monocytes, while PGE2 alone sufficiently increases IL-10 secretion from macrophages. Treatment with agonists activating PGE2 receptors EP2/EP4, achieves the similar IL-10-inducing effects on myeloid cells. Zta transactivates the GM-CSF promoter in NPC cells, through a Zta-responsive region that has been narrowed to -161 to -5. On the other hand, Zta induces PGE2 production in NPC cells through upregulation of an upstream enzyme cyclooxygenase-2 (COX-2), in that siRNA or a COX-2 inhibitor blocks the Zta-mediated induction of PGE2. Similar results are observed in NPC cells with EBV lytic infection. EBV reactivation can promote NPC cells to express GM-CSF, COX-2 and PGE2 and enhance IL-10 secretion from myeloid cells. The induction of immunomodulators and IL-10 secretion can be inhibited when EBV reactivation is blocked by Zta siRNA. This study suggests that, through Zta-induced immunomodulators, EBV-infected NPC cells may direct infiltrating myeloid immune cells to secrete the immunosuppressive cytokine IL-10, establishing a tumor microenvironment that favors evasion of anti-cancer or anti-viral immunity.

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