Giffin Louise, West John A, Damania Blossom
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
mBio. 2015 Dec 8;6(6):e01499-15. doi: 10.1128/mBio.01499-15.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of human Kaposi's sarcoma, a tumor that arises from endothelial cells, as well as two B cell lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman's disease. KSHV utilizes a variety of mechanisms to evade host immune responses and promote cellular transformation and growth in order to persist for the life of the host. A viral homolog of human interleukin-6 (hIL-6) named viral interleukin-6 (vIL-6) is encoded by KSHV and expressed in KSHV-associated cancers. Similar to hIL-6, vIL-6 is secreted, but the majority of vIL-6 is retained within the endoplasmic reticulum, where it can initiate functional signaling through part of the interleukin-6 receptor complex. We sought to determine how intracellular vIL-6 modulates the host endothelial cell environment by analyzing vIL-6's impact on the endothelial cell transcriptome. vIL-6 significantly altered the expression of many cellular genes associated with cell migration. In particular, vIL-6 upregulated the host factor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) at the protein and message levels. CEACAM1 has been implicated in tumor invasion and metastasis and promotes migration and vascular remodeling in endothelial cells. We report that vIL-6 upregulates CEACAM1 by a STAT3-dependent mechanism and that CEACAM1 promotes vIL-6-mediated migration. Furthermore, latent and de novo KSHV infections of endothelial cells also induce CEACAM1 expression. Collectively, our data suggest that vIL-6 modulates endothelial cell migration by upregulating the expression of cellular factors, including CEACAM1.
Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with the development of three human malignancies, Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. KSHV expresses many factors that enable the virus to manipulate the host environment in order to persist and induce disease. The viral interleukin-6 (vIL-6) produced by KSHV is structurally and functionally homologous to the human cytokine interleukin-6, except that vIL-6 is secreted slowly and functions primarily from inside the host cell. To investigate the unique intracellular role of vIL-6, we analyzed the impact of vIL-6 on endothelial cell gene expression. We report that vIL-6 significantly alters the expression of genes associated with cell movement, including that for CEACAM1. The gene for CEACAM1 was upregulated by vIL-6 and by latent and primary KSHV infection and promotes vIL-6-mediated endothelial cell migration. This work advances the field's understanding of vIL-6 function and its contribution to KSHV pathogenesis.
卡波西肉瘤相关疱疹病毒（KSHV）是人类卡波西肉瘤的病原体，卡波西肉瘤是一种起源于内皮细胞的肿瘤，同时也是两种B细胞淋巴增殖性疾病——原发性渗出性淋巴瘤和多中心Castleman病的病原体。KSHV利用多种机制逃避宿主免疫反应并促进细胞转化和生长，以便在宿主体内存活。一种名为病毒白细胞介素-6（vIL-6）的人类白细胞介素-6（hIL-6）病毒同源物由KSHV编码并在与KSHV相关的癌症中表达。与hIL-6相似，vIL-6也会分泌，但大多数vIL-6保留在内质网中，在那里它可以通过白细胞介素-6受体复合物的一部分启动功能性信号传导。我们试图通过分析vIL-6对内皮细胞转录组的影响来确定细胞内vIL-6如何调节宿主内皮细胞环境。vIL-6显著改变了许多与细胞迁移相关的细胞基因的表达。特别是，vIL-6在蛋白质和信息水平上上调了宿主因子癌胚抗原相关细胞粘附分子1（CEACAM1）。CEACAM1与肿瘤侵袭和转移有关，并促进内皮细胞的迁移和血管重塑。我们报告称，vIL-6通过一种依赖STAT3的机制上调CEACAM1，并且CEACAM1促进vIL-6介导的迁移。此外，内皮细胞的潜伏性和原发性KSHV感染也会诱导CEACAM1表达。总体而言，我们的数据表明vIL-6通过上调包括CEACAM1在内的细胞因子表达来调节内皮细胞迁移。
卡波西肉瘤相关疱疹病毒（KSHV）与三种人类恶性肿瘤——卡波西肉瘤、多中心Castleman病和原发性渗出性淋巴瘤的发生有关。KSHV表达许多因子，使病毒能够操纵宿主环境以持续存在并诱发疾病。KSHV产生的病毒白细胞介素-6（vIL-6）在结构和功能上与人类细胞因子白细胞介素-6同源，只是vIL-6分泌缓慢，主要在宿主细胞内发挥作用。为了研究vIL-6独特的细胞内作用，我们分析了vIL-6对内皮细胞基因表达的影响。我们报告称，vIL-6显著改变了与细胞运动相关的基因表达，包括CEACAM1的基因表达。CEACAM1基因被vIL-6以及潜伏性和原发性KSHV感染上调，并促进vIL-6介导的内皮细胞迁移。这项工作推进了该领域对vIL-6功能及其对KSHV发病机制贡献的理解。
