Department of Microbiology and Immunology, College of Graduate Studies, Midwestern University, Downers Grove, Illinois.
Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois.
J Med Virol. 2019 May;91(5):845-855. doi: 10.1002/jmv.25381. Epub 2019 Jan 4.
The incidence of Hodgkin's lymphoma (HL) is growing due to an increase in Epstein-Barr virus (EBV)-associated HL in AIDS patients. The HL tumor microenvironment is vital for the survival of the malignant Hodgkin-Reed Sternberg (HRS) cells of HL, which express the EBV protein latent membrane protein 2A (LMP2A). While previous work shows that LMP2A mimics B-cell receptor (BCR) signaling to promote the survival of HRS cells, the ability of LMP2A to establish and maintain the tumor microenvironment through the production of chemokines remains unknown. Since BCR signaling induces the production of the chemokine macrophage inflammatory protein-1α (MIP-1α), and since LMP2A is a BCR mimic, we hypothesized that LMP2A increases MIP-1α levels. A comparison of multiple LMP2A-negative and -positive cell lines demonstrates that LMP2A increases MIP-1α. Additionally, LMP2A-mutant cell lines and pharmacologic inhibitors indicate that LMP2A activates a Syk/PI3K/NF-κB pathway to enhance MIP-1α. Finally, based on the finding that an NF-κB inhibitor decreased MIP-1α RNA/protein in LMP2A-positive cells, we are the first to demonstrate that LMP2A increases the nuclear localization of the NF-κB p65 subunit using DNA-binding assays and confocal microscopy in human B cells. These findings not only have implications for the treatment of HL, but also other LMP2A-expressing B-cell tumors that overexpress NF-κB.
由于艾滋病患者中 EBV 相关 HL 的增加，霍奇金淋巴瘤 (HL) 的发病率正在上升。HL 肿瘤微环境对于 HL 恶性霍奇金-里德斯特恩伯格 (HRS) 细胞的存活至关重要，这些细胞表达 EBV 蛋白潜伏膜蛋白 2A (LMP2A)。虽然之前的工作表明 LMP2A 通过模拟 B 细胞受体 (BCR) 信号来促进 HRS 细胞的存活，但 LMP2A 通过产生趋化因子来建立和维持肿瘤微环境的能力尚不清楚。由于 BCR 信号诱导趋化因子巨噬细胞炎性蛋白-1α (MIP-1α) 的产生，并且由于 LMP2A 是 BCR 的模拟物，我们假设 LMP2A 增加了 MIP-1α 的水平。对多个 LMP2A 阴性和阳性细胞系的比较表明，LMP2A 增加了 MIP-1α。此外，LMP2A 突变细胞系和药理抑制剂表明，LMP2A 通过激活 Syk/PI3K/NF-κB 途径来增强 MIP-1α。最后，基于发现 NF-κB 抑制剂可降低 LMP2A 阳性细胞中 MIP-1α RNA/蛋白的发现，我们首次使用 DNA 结合测定法和共聚焦显微镜在人 B 细胞中证明 LMP2A 增加了 NF-κB p65 亚基的核定位。这些发现不仅对 HL 的治疗具有重要意义，而且对其他过度表达 NF-κB 的 LMP2A 表达 B 细胞肿瘤也具有重要意义。
