Intracellular Signaling Mechanisms and Activities of Human Herpesvirus 8 Interleukin-6
Intracellular Signaling Mechanisms and Activities of Human Herpesvirus 8 Interleukin-6
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DOI：
10.1128/jvi.01517-08
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发表时间：
2009-01-15
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：
Chen, Daming;Sandford, Gordon;Nicholas, John
人类疱疹病毒 8 (HHV-8) 编码的病毒白细胞介素 6 (vIL-6) 由于其增殖和存活作用以及其血管生成特性而被认为是病毒相关肿瘤的关键因素。 vIL-6 和人 IL-6 (hIL-6) 之间的主要区别在于，vIL-6 独特地大部分被保留并可以在细胞内发出信号。虽然 vIL-6 通常被认为是一种裂解基因，但一些报告指出，在没有其他裂解基因表达的情况下，它在潜伏感染的原发性渗出性淋巴瘤 (PEL) 培养物中低水平表达。因此，病毒细胞因子的细胞内自分泌信号转导可能与潜伏感染细胞的生长和存活以及发病机制特别相关。在这里，我们报告大多数细胞内 vIL-6 位于内质网 (ER) 中，通过该区室中的 gp130 信号转导器发出信号，并且独立于 hIL-6 信号转导所需的 IL-6 受体的 gp80 α 亚基进行信号传递。结合 ER 保留的 vIL-6 和 hIL-6 的信号传导和生物测定证实了 vIL-6 活性，特别是在该隔室中。 PEL 细胞中 vIL-6 表达的敲低导致正常培养物中细胞生长显着减少，与细胞外细胞因子无关。这可以通过通过仅 ER 保留的 vIL-6 的病毒载体重新引入来逆转。这些数据表明，在病毒生物学中，vIL-6可能通过内分泌信号以自分泌方式支持潜伏感染HHV-8的细胞的生长和存活，并且这些活性可能有助于潜伏感染细胞的维持和病毒诱导的肿瘤形成。
Human herpesvirus 8 (HHV-8)-encoded viral interleukin-6 (vIL-6) has been implicated as a key factor in virus-associated neoplasia because of its proproliferative and survival effects and also in view of its angiogenic properties. A major difference between vIL-6 and human IL-6 (hIL-6) is that vIL-6, uniquely, is largely retained and can signal intracellularly. While vIL-6 is generally considered to be a lytic gene, several reports have noted its low-level expression in latently infected primary effusion lymphoma (PEL) cultures, in the absence of other lytic gene expression. Thus, intracellular autocrine signal transduction by the viral cytokine may be of particular relevance to the growth and survival of latently infected cells and to pathogenesis. Here we report that most intracellular vIL-6 is located in the endoplasmic reticulum (ER), signals via the gp130 signal transducer in this compartment, and does so independently of the gp80 alpha-subunit of the IL-6 receptor, required for hIL-6 signal transduction. Signaling and biological assays incorporating ER-retained vIL-6 and hIL-6 confirmed vIL-6 activity, specifically, in this compartment. Knockdown of vIL-6 expression in PEL cells led to markedly reduced cell growth in normal culture, independently of extracellular cytokines. This could be reversed by reintroduction via virus vector of exclusively ER-retained vIL-6. These data indicate that in virus biology vIL-6 may act to support the growth and survival of cells latently infected with HHV-8 in an autocrine manner via intracrine signaling and that these activities may contribute to the maintenance of latently infected cells and to virus-induced neoplasia.