Activation of Akt through gp130 receptor signaling is required for Kaposi's sarcoma-associated herpesvirus-induced lymphatic reprogramming of endothelial cells
Activation of Akt through gp130 receptor signaling is required for Kaposi's sarcoma-associated herpesvirus-induced lymphatic reprogramming of endothelial cells
复制标题
DOI：
10.1128/jvi.00766-08
复制
发表时间：
2008-09-01
影响因子：
5.4
通讯作者：
Lagunoff, Michael
中科院分区：
文献类型：
--
作者：
Morris, Valerie A.;Punjabi, Almira S.;Lagunoff, Michael
卡波西肉瘤（KS）是全世界艾滋病患者最常见的肿瘤。 KS 相关疱疹病毒 (KSHV) 是这种高度血管化皮肤肿瘤的感染原因。 KS 病变内发现的主要细胞类型是梭形细胞，潜伏感染 KSHV，并具有血液和淋巴内皮细胞的标记。在发育过程中，淋巴内皮细胞从先前存在的血液内皮细胞分化。有趣的是，KSHV感染血液内皮细胞会诱导淋巴管内皮细胞分化。在这里，我们表明 KSHV 基因表达对于维持淋巴标志物血管内皮生长因子受体 3 (VEGFR-3) 和足足蛋白的表达是必需的。 KSHV 感染激活内皮细胞中的许多细胞信号传导途径，并通过 gp130 受体（细胞因子白细胞介素 6 家族的常见受体）持续激活 STAT3。我们发现 KSRV 感染还会激活潜伏感染内皮细胞中的磷脂酰肌醇 3-OH-激酶 (PI3K)/Akt 细胞信号传导通路，并且 gp130 受体信号传导对于 Akt 激活是必需的。使用药物抑制剂和小干扰RNA敲低，我们发现gp130受体介导的JAK2/STAT3和PI3K/Akt细胞信号通路的激活对于KSRV诱导的内皮细胞淋巴重编程是必要的。淋巴管内皮细胞特异性转录因子 Prox1 的诱导也参与 KSHV 诱导的淋巴管重编程。 gp130受体信号传导的激活是血液内皮细胞分化为淋巴管内皮细胞的新机制，可能与淋巴管内皮细胞的发育或病理分化以及KSRV发病机制有关。
Kaposi's sarcoma (KS) is the most common tumor of AIDS patients worldwide. KS-associated herpesvirus (KSHV) is the infectious cause of this highly vascularized skin tumor. The main cell type found within a KS lesion, the spindle cell, is latently infected with KSHV and has markers of both blood and lymphatic endothelial cells. During development, lymphatic endothelial cells differentiate from preexisting blood endothelial cells. Interestingly, KSHV infection of blood endothelial cells induces lymphatic endothelial cell differentiation. Here, we show that KSHV gene expression is necessary to maintain the expression of the lymphatic markers vascular endothelial growth factor receptor 3 (VEGFR-3) and podoplanin. KSHV infection activates many cell signaling pathways in endothelial cells and persistently activates STAT3 through the gp130 receptor, the common receptor of the interleukin 6 family of cytokines. We find that KSRV infection also activates the phosphatidylinositol 3-OH-kinase (PI3K)/Akt cell signaling pathway in latently infected endothelial cells and that gp130 receptor signaling is necessary for Akt activation. Using both pharmacological inhibitors and small interfering RNA knockdown, we show that the gp130 receptor-mediated activation of both the JAK2/STAT3 and PI3K/Akt cell signaling pathways is necessary for KSRV-induced lymphatic reprogramming of endothelial cells. The induction of the lymphatic endothelial cell-specific transcription factor Prox1 is also involved in KSHV-induced lymphatic reprogramming. The activation of gp130 receptor signaling is a novel mechanism for the differentiation of blood endothelial cells into lymphatic endothelial cells and may be relevant to the developmental or pathological differentiation of lymphatic endothelial cells as well as to KSRV pathogenesis.