Role of Human Herpesvirus 8 Interleukin-6-Activated gp130 Signal Transducer in Primary Effusion Lymphoma Cell Growth and Viability
Role of Human Herpesvirus 8 Interleukin-6-Activated gp130 Signal Transducer in Primary Effusion Lymphoma Cell Growth and Viability
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DOI：
10.1128/jvi.02047-13
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发表时间：
2013-10-01
影响因子：
5.4
通讯作者：
Nicholas, John
中科院分区：
文献类型：
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作者：
Cousins, Emily;Nicholas, John
人类疱疹病毒 8 (HHV-8) 感染与卡波西肉瘤、原发性渗出性淋巴瘤 (PEL) 和多中心卡斯尔曼病有关。 HHV-8 编码的病毒白细胞介素 6 (vIL-6) 被认为通过增殖、抗凋亡和促血管生成活性促进发病机制。在 PEL 细胞中，vIL-6 在病毒潜伏期期间以功能量产生，并促进这些细胞的生长，介导其主要位于内质网 (ER) 的活性。 vIL-6 的活性部分取决于其与维生素 K 环氧化物还原酶复合物亚基 1 (VKORC1) 剪接变体（称为 VKORC1 变体 2 (VKORC1v2)）的相互作用。在这里，我们报告说，IL-6 信号转导器 gp130 可以支持来自 ER 的 vIL-6 信号传导，也是最佳 PEL 细胞生长和活力所必需的。在 gp130 刺激后磷酸化的激活的细胞外调节激酶 (ERK) 1 和 2 以及信号转导子和转录激活子 1 (STAT1) 和 STAT3 的水平在 gp130 耗尽的 BCBL-1 和 BC-1 细胞中降低。在 JSC-1 和 BC-3 细胞中也检测到 STAT 激活减弱。 gp130 消耗对生长的影响可以通过靶向 ERK 1 和 2 的短发夹 RNA 或通过消耗 STAT3 来模拟。最后，抑制内质网室内的 vIL-6-gp130 关联可抑制细胞增殖和活力，反映了 gp130 耗竭的影响。综合起来，这些数据表明，除了 VKORC1v2 之外，gp130 对于正常 PEL 细胞的生长和存活至关重要，并且内质网定位的 vIL-6-gp130 相互作用对于这些活动至关重要。靶向细胞内 vIL-6-gp130 相互作用可能提供 PEL 治疗的一种方法。
Human herpesvirus 8 (HHV-8) infection is associated with Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. HHV-8-encoded viral interleukin-6 (vIL-6) is believed to contribute to pathogenesis via proproliferative, antiapoptotic, and proangiogenic activities. In PEL cells, vIL-6 is produced in functional amounts during viral latency and promotes the growth of these cells, mediating its activity from the endoplasmic reticulum (ER), where it is predominantly localized. This vIL-6 activity is dependent, in part, on its interaction with a splice variant of vitamin K epoxide reductase complex subunit 1 (VKORC1), termed VKORC1 variant 2 (VKORC1v2). Here we report that the IL-6 signal transducer, gp130, which can support vIL-6 signaling from the ER, is also required for optimal PEL cell growth and viability. Levels of activated extracellular regulated kinases (ERKs) 1 and 2 and signal transducer and activator of transcription 1 (STAT1) and STAT3, phosphorylated following gp130 stimulation, were reduced in gp130-depleted BCBL-1 and BC-1 cells. Diminished STAT activation was also detected in JSC-1 and BC-3 cells. Effects of gp130 depletion on growth could be mimicked by short hairpin RNA targeting of ERKs 1 and 2 or by depletion of STAT3. Finally, inhibition of vIL-6-gp130 association specifically within the ER compartment suppressed cell proliferation and viability, mirroring the effects of gp130 depletion. Combined, these data demonstrate that gp130, in addition to VKORC1v2, is essential for normal PEL cell growth and survival and that ER-localized vIL-6-gp130 interactions are critical for these activities. Targeting of intracellular vIL-6-gp130 interactions could potentially provide a means of PEL therapy.