STAT3 is constitutively activated in chronic active Epstein-Barr virus infection and can be a therapeutic target.
STAT3 is constitutively activated in chronic active Epstein-Barr virus infection and can be a therapeutic target.
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DOI：
10.18632/oncotarget.25780
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发表时间：
2018-07-24
期刊：
影响因子：
--
通讯作者：
Arai, Ayako
中科院分区：
文献类型：
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作者：
Onozawa, Erika;Shibayama, Haruna;Arai, Ayako
慢性活动性EB病毒感染（CAEBV）是一种淋巴组织增生性疾病，其特征是EBV感染的T细胞或NK细胞的克隆性增殖，并与严重的全身炎症有关。本研究旨在通过对STAT 3的研究来阐明CAEBV的发病机制。我们确定，STAT 3在EBV阳性T细胞系或NK细胞系中被组成性激活。我们还确定，STAT 3被激活的外周血单个核细胞（PBMC）含有EBV感染的克隆增殖T细胞或NK细胞在6/7例CAEBV患者。我们进行了STAT 3 Src同源性2（SH 2）结构域的直接测序，该结构域先前已被报道在T细胞或NK细胞肿瘤中发生突变。在CAEBV患者中未检测到STAT 3 SH 2结构域的突变。接下来，我们研究了ruxolitinib的作用，ruxolitinib是JAK 1和JAK 2的抑制剂，它磷酸化并激活STAT 3。Ruxolitinib抑制EBV阳性T细胞或NK细胞系中STAT 3的磷酸化。Ruxolitinib还降低了来自CAEBV患者的EBV阳性T或NK细胞系和PBMC的活细胞数。此外，ruxolitinib抑制细胞系和CAEBV患者衍生细胞中炎性细胞因子的产生。总之，组成性激活的STAT 3，促进生存和细胞因子的产生，可能是CAEBV的治疗靶点。
Chronic active Epstein-Barr virus infection (CAEBV) is a lymphoproliferative disorder characterized by the clonal proliferation of EBV-infected T or NK cells and is related to severe systemic inflammation. This study aims to investigate STAT3 to elucidate the mechanism underlying the CAEBV development. We determined that STAT3 was constitutively activated in EBV-positive T- or NK-cell lines. We also determined that STAT3 was activated in the peripheral blood mononuclear cells (PBMCs) containing EBV-infected clonally proliferating T or NK cells in six of seven patients with CAEBV. We conducted direct sequencing of the STAT3 Src homology 2 (SH2) domain, which has previously been reported to be mutated in T- or NK-cell neoplasms. No mutation was detected in the STAT3 SH2 domain in patients with CAEBV. Next, we investigated the effects of ruxolitinib, an inhibitor of both JAK1 and JAK2, which phosphorylates and activates STAT3. Ruxolitinib suppressed the phosphorylation of STAT3 in EBV-positive T- or NK-cell lines. Ruxolitinib also decreased the viable cell number of EBV-positive T- or NK-cell lines and PBMCs from patients with CAEBV. Furthermore, ruxolitinib suppressed the production of inflammatory cytokines in the cell lines and CAEBV patient-derived cells. In conclusion, constitutively activated STAT3, which promotes survival and cytokine production, could be a therapeutic target for CAEBV.