Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection
Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection
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DOI：
10.1182/bloodadvances.2020002417
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发表时间：
2021-03-31
期刊：
影响因子：
7.5
通讯作者：
Arai, Ayako
中科院分区：
文献类型：
--
作者：
Yoshimori, Mayumi;Shibayama, Haruna;Arai, Ayako
系统性慢性活动性爱泼斯坦- ban病毒（EBV; sCAEBV）感染，T-和自然杀伤（NK）细胞型（sCAEBV），是一种致命的疾病，伴随EBV感染的T或NK细胞克隆增殖的持续炎症。目前的化疗不足以解决疾病活动和清除sCAEBV感染细胞。目前建立的根除感染细胞的治疗策略是异体造血干细胞移植。在本研究中，我们重点研究了蛋白酶体抑制剂硼替佐米对该病的影响。硼替佐米抑制EBV+ T-或NK细胞系以及感染EBV的T或NK细胞的外周血单核细胞的存活并诱导凋亡。硼替佐米增强内质网应激诱导的结合免疫球蛋白蛋白/78-kDa糖调蛋白（Bip/GRP78）表达，激活细胞凋亡促进分子INK和p38。硼替佐米抑制促生存分子NF-kappa B的激活，该分子在EBV+ T-或nk细胞系中构成性激活。此外，定量逆转录聚合酶链反应表明，硼替佐米抑制了患者EBV+ T或NK细胞中促炎细胞因子肿瘤坏死因子α (inf - α)和干扰素γ (ifn - γ)的信使RNA表达。最后，我们通过静脉注射患者细胞产生的sCAEBV异种移植模型来检测硼替佐米的作用。通过腹腔注射硼替佐米可显著降低外周血EBVDNA载量和模型肝脏中ebv感染细胞的浸润。硼替佐米治疗后，大鼠血清tnf - α和ifn - γ浓度降低。我们的研究结果将转化为sCAEBV的治疗，不仅可以减少肿瘤细胞的数量，还可以抑制炎症。
Systemic chronic active Epstein-Ban virus (EBV; sCAEBV) infection, T- and natural killer (NK)-cell type (sCAEBV), is a fatal disorder accompanied by persisting inflammation harboring clonal proliferation of EBV-infected T or NK cells. Today's chemotherapy is insufficient to resolve disease activity and to rid infected cells of sCAEBV. The currently established treatment strategy for eradicating infected cells is allogeneic hematopoietic stem cell transplantation. In this study, we focused on the effects of proteasome inhibitor bortezomib on the disease. Bortezomib suppressed survival and induced apoptosis of EBV+ T- or NK-cell lines and peripheral mononuclear cells containing EBV-infected T or NK cells of sCAEBV patients. Bortezomib enhanced binding immunoglobulin protein/78-kDa glucoseregulated protein (Bip/GRP78) expression induced by endoplasmic reticulum stress and activated apoptosis-promoting molecules INK and p38 in the cell lines. Bortezomib suppressed the activation of survival-promoting molecule NF-kappa B, which was constitutively activated in EBV+ T- or NK-cell lines. Furthermore, quantitative reverse transcription-polymerase chain reaction demonstrated that bortezomib suppressed messenger RNA expression of proinflammatory cytokines tumor necrosis factor alpha (INF-alpha) and interferon -gamma (IFN-gamma) in EBV+ T or NK cells from the patients. Finally, we examined the effects of bortezomib using xenograft models of sCAEBV generated by IV injection of patients' cells. The intraperitoneal administration of bortezomib significantly reduced EBVDNA load in peripheral blood and the infiltration of EBV-infected cells in the models' livers. Moreover, the serum concentration of TNF-alpha and IFN-gamma decreased after bortezomib treatment to the models. Our findings will be translated into the treatment of sCAEBV not only to reduce the number of tumor cells but also to suppress inflammation.