State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China Department of Clinic Lab, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
J Virol. 2014 Jun;88(12):6660-71. doi: 10.1128/JVI.03678-13. Epub 2014 Apr 2.
Epstein-Barr virus (EBV) infection has been observed in tumor-infiltrated macrophages, but its infection effects on macrophage immune functions are poorly understood. Here, we showed that some macrophages in the tumor stroma of nasopharyngeal carcinoma (NPC) tissue expressed the immunosuppressive protein indoleamine 2,3-dioxygenase (IDO) more strongly than did tumor cells. EBV infection induced mRNA, protein, and enzymatic activity of IDO in human monocyte-derived macrophages (MDMs). Infection increased the production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), whereas the neutralizing antibodies against TNF-α and IL-6 inhibited IDO induction. EBV infection also activated the mitogen-activated protein kinase (MAPK) p38 and NF-κB, and the inhibition of these two pathways with SB202190 and SN50 almost abrogated TNF-α and IL-6 production and inhibited IDO production. Moreover, the activation of IDO in response to EBV infection of MDMs suppressed the proliferation of T cells and impaired the cytotoxic activity of CD8(+) T cells, whereas the inhibition of IDO activity with 1-methyl-l-tryptophan (1-MT) did not affect T cell proliferation and function. These findings indicate that EBV-induced IDO expression in MDMs is substantially mediated by IL-6- and TNF-α-dependent mechanisms via the p38/MAPK and NF-κB pathways, suggesting that a possible role of EBV-mediated IDO expression in tumor stroma of NPC may be to create a microenvironment of suppressed T cell immune responses.
CD8(+) cytotoxic T lymphocytes (CTLs) play an important role in the control of viral infections and destroy tumor cells. Activation of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in cancer tissues facilitates immune escape by the impairment of CTL functions. IDO expression was observed in some macrophages of the tumor stroma of nasopharyngeal carcinoma (NPC) tissue, and IDO could be induced in Epstein-Barr virus (EBV)-infected human monocyte-derived macrophages (MDMs). NPC cells and macrophages have been found to produce IDO in a gamma interferon (IFN-γ)-dependent manner. Instead, EBV-induced IDO expression in MDMs is substantially mediated by IL-6- and TNF-α-dependent mechanisms via the p38/MAPK and NF-κB pathways, which suppressed the proliferation of T cells and impaired the cytotoxic activity of CD8(+) T cells. This finding provides a new interpretation of the mechanism of immune escape of EBV and shows the immunosuppressive role of EBV-mediated IDO expression in tumor stroma of NPC.
已观察到肿瘤浸润的巨噬细胞中存在 Epstein-Barr 病毒 (EBV) 感染，但 EBV 对巨噬细胞免疫功能的感染影响尚不清楚。在这里，我们发现鼻咽癌 (NPC) 组织肿瘤基质中的一些巨噬细胞表达的免疫抑制蛋白吲哚胺 2,3-双加氧酶 (IDO) 比肿瘤细胞更强。EBV 感染诱导人单核细胞衍生的巨噬细胞 (MDM) 中 IDO 的 mRNA、蛋白和酶活性。感染增加了肿瘤坏死因子-α (TNF-α) 和白细胞介素-6 (IL-6) 的产生，而针对 TNF-α 和 IL-6 的中和抗体抑制了 IDO 的诱导。EBV 感染还激活了丝裂原激活蛋白激酶 (MAPK) p38 和 NF-κB，用 SB202190 和 SN50 抑制这两条通路几乎完全阻断了 TNF-α 和 IL-6 的产生，并抑制了 IDO 的产生。此外，EBV 感染 MDM 后 IDO 的激活抑制了 T 细胞的增殖，并损害了 CD8(+) T 细胞的细胞毒性活性，而用 1-甲基-L-色氨酸 (1-MT) 抑制 IDO 活性则不影响 T 细胞的增殖和功能。这些发现表明，EBV 诱导的 MDM 中 IDO 的表达主要是通过依赖于 IL-6 和 TNF-α 的机制通过 p38/MAPK 和 NF-κB 途径介导的，提示 EBV 介导的 NPC 肿瘤基质中 IDO 表达的可能作用可能是创建受抑制的 T 细胞免疫反应的微环境。
CD8(+) 细胞毒性 T 淋巴细胞 (CTL) 在控制病毒感染和破坏肿瘤细胞方面发挥着重要作用。癌症组织中色氨酸分解酶吲哚胺 2,3-双加氧酶 (IDO) 的激活通过损害 CTL 功能促进免疫逃逸。已观察到鼻咽癌 (NPC) 组织肿瘤基质中的一些巨噬细胞中存在 IDO，EBV 可诱导 Epstein-Barr 病毒 (EBV) 感染的人单核细胞衍生的巨噬细胞 (MDM) 中 IDO 的表达。NPC 细胞和巨噬细胞已被发现以干扰素-γ (IFN-γ) 依赖的方式产生 IDO。相反，EBV 诱导的 MDM 中 IDO 的表达主要是通过依赖于 IL-6 和 TNF-α 的机制通过 p38/MAPK 和 NF-κB 途径介导的，这抑制了 T 细胞的增殖并损害了 CD8(+) T 细胞的细胞毒性活性。这一发现为 EBV 免疫逃逸的机制提供了新的解释，并表明 EBV 介导的 NPC 肿瘤基质中 IDO 表达的免疫抑制作用。
