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 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 Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes

“…RNA was extracted from monocytes at 48 h after infection with either intact KSHV or UV-inactivated KSHV. The levels of viral interleukin-6 (vIL-6) were quantified via real-time PCR for message levels at 48 h postinfection ( 47 ). KSHV vIL-6 at 48 hpi showed increasing levels correlated with increasing dosages of intact KSHV ( Fig.…”

Modulation of oncogenic signaling networks by Kaposi’s sarcoma-associated herpesvirus

“…The latency locus encodes the latent proteins, ORF71 to ORF73, the kaposins, and twelve microRNAs (miRNAs) (Ye et al, 2011). During latency, lytic gene expression is suppressed; however, several proteins highly expressed in the lytic cycle are present at low levels during latency such as K1 and vIL-6 (Bhatt et al, 2012; Giffin et al, 2015). The viral genome is tethered as an episome to the host chromosome by ORF73/LANA (latency-associated nuclear antigen) and is replicated in coordination with the host genome using host replication machinery (Ye et al, 2011).…”

“…Pathways upregulated during KSHV infection include the NF-κB, phosphatidylinositol-4,5-bisphosphate 3 kinases (PI3K)/ protein kinase B (Akt)/mammalian target of rapamycin (mTOR), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and mitogen-activated protein kinase (MAPK) pathways (Brinkmann et al, 2003; Xie et al, 2008; Bhatt et al, 2010; Giffin et al, 2015). These pathways rely on kinases to induce a signaling cascade by phosphorylating proteins to recruit and/or alter activity of target substrates.…”

“…In endothelial cells, vIL-6 activates gp130 leading to the upregulation of several lymphatic markers including podoplanin in a Akt- and STAT3-dependent manner (Bhatt et al, 2012). Unlike human IL-6, vIL-6 can upregulate the expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) to promote endothelial cell migration (Giffin et al, 2015). Stably-expressing vIL-6 NIH3T3 cells can also induce tumor formation in nude mice and transgenic mice expressing vIL-6 exhibit MCD-like disease (Bhatt et al, 2012; Zhu et al, 2014).…”

Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma

“…Cell Culture. Except for OCl-Ly1 and OCl-Ly3, NHL cell lines were grown in a similar manner as described previously (33,76,77). OCl-Ly1 and OCl-Ly3 were grown in Iscove's modified Dulbecco's medium (IMDM), 20% human AB serum (Sigma-Aldrich, H4522), 1% penicillin-streptomycin, and 75 μM β-mercaptoethanol (Gibco, 21985-023).…”