Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration

ABSTRACT 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 var...

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Autores principales:	Louise Giffin, John A. West, Blossom Damania
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3e379f872e4c47029996c2bc516aa526
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spelling	oai:doaj.org-article:3e379f872e4c47029996c2bc516aa5262021-11-15T15:41:24ZKaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration10.1128/mBio.01499-152150-7511https://doaj.org/article/3e379f872e4c47029996c2bc516aa5262015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01499-15https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Louise GiffinJohn A. WestBlossom DamaniaAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Louise Giffin John A. West Blossom Damania Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration
description	ABSTRACT 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. IMPORTANCE 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.
format	article
author	Louise Giffin John A. West Blossom Damania
author_facet	Louise Giffin John A. West Blossom Damania
author_sort	Louise Giffin
title	Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration
title_short	Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration
title_full	Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration
title_fullStr	Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration
title_full_unstemmed	Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration
title_sort	kaposi's sarcoma-associated herpesvirus interleukin-6 modulates endothelial cell movement by upregulating cellular genes involved in migration
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/3e379f872e4c47029996c2bc516aa526
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Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration

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