Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
J Virol. 2013 Aug;87(16):9041-52. doi: 10.1128/JVI.00541-13. Epub 2013 Jun 12.
Epstein-Barr virus (EBV) alters the regulation and expression of a variety of cytokines in its host cells to modulate host immune surveillance and facilitate viral persistence. Using cytokine antibody arrays, we found that, in addition to the cytokines reported previously, two chemotactic cytokines, CCL3 and CCL4, were induced in EBV-infected B cells and were expressed at high levels in all EBV-immortalized lymphoblastoid cell lines (LCLs). Furthermore, EBV latent membrane protein 1 (LMP1)-mediated Jun N-terminal protein kinase activation was responsible for upregulation of CCL3 and CCL4. Inhibition of CCL3 and CCL4 in LCLs using a short hairpin RNA approach or by neutralizing antibodies suppressed cell proliferation and caused apoptosis, indicating that autocrine CCL3 and CCL4 are required for LCL survival and growth. Importantly, significant amounts of CCL3 were detected in EBV-positive plasma from immunocompromised patients, suggesting that EBV modulates this chemokine in vivo. This study reveals the regulatory mechanism and a novel function of CCL3 and CCL4 in EBV-infected B cells. CCL3 might be useful as a therapeutic target in EBV-associated lymphoproliferative diseases and malignancies.
EB 病毒（EBV）改变了宿主细胞中多种细胞因子的调节和表达，以调节宿主免疫监视并促进病毒持续存在。通过细胞因子抗体阵列，我们发现，除了之前报道的细胞因子外，两种趋化细胞因子 CCL3 和 CCL4 在 EBV 感染的 B 细胞中被诱导，并在所有 EBV 永生化淋巴母细胞系（LCL）中高水平表达。此外，EBV 潜伏膜蛋白 1（LMP1）介导的 Jun N 末端蛋白激酶激活负责上调 CCL3 和 CCL4。使用短发夹 RNA 方法或中和抗体抑制 LCL 中的 CCL3 和 CCL4，可抑制细胞增殖并引起细胞凋亡，表明自分泌 CCL3 和 CCL4 是 LCL 存活和生长所必需的。重要的是，在免疫功能低下患者的 EBV 阳性血浆中检测到大量的 CCL3，提示 EBV 在体内调节这种趋化因子。本研究揭示了 CCL3 和 CCL4 在 EBV 感染的 B 细胞中的调节机制和新功能。CCL3 可能是 EBV 相关淋巴增生性疾病和恶性肿瘤的治疗靶点。
