Abstract
Kaposi's sarcoma (KS), an enigmatic endothelial cell vascular neoplasm, is characterized by the proliferation of spindle shaped endothelial cells, inflammatory cytokines (ICs), growth factors (GFs) and angiogenic factors. KSHV is etiologically linked to KS and expresses its latent genes in KS lesion endothelial cells. Primary infection of human micro vascular endothelial cells (HMVEC-d) results in the establishment of latent infection and reprogramming of host genes, and cyclooxygenase-2 (COX-2) is one of the highly up-regulated genes. Our previous study suggested a role for COX-2 in the establishment and maintenance of KSHV latency. Here, we examined the role of COX-2 in the induction of ICs, GFs, angiogenesis and invasive events occurring during KSHV de novo infection of endothelial cells. A significant amount of COX-2 was detected in KS tissue sections. Telomerase-immortalized human umbilical vein endothelial cells supporting KSHV stable latency (TIVE-LTC) expressed elevated levels of functional COX-2 and microsomal PGE2 synthase (m-PGES), and secreted the predominant eicosanoid inflammatory metabolite PGE2. Infected HMVEC-d and TIVE-LTC cells secreted a variety of ICs, GFs, angiogenic factors and matrix metalloproteinases (MMPs), which were significantly abrogated by COX-2 inhibition either by chemical inhibitors or by siRNA. The ability of these factors to induce tube formation of uninfected endothelial cells was also inhibited. PGE2, secreted early during KSHV infection, profoundly increased the adhesion of uninfected endothelial cells to fibronectin by activating the small G protein Rac1. COX-2 inhibition considerably reduced KSHV latent ORF73 gene expression and survival of TIVE-LTC cells. Collectively, these studies underscore the pivotal role of KSHV induced COX-2/PGE2 in creating KS lesion like microenvironment during de novo infection. Since COX-2 plays multiple roles in KSHV latent gene expression, which themselves are powerful mediators of cytokine induction, anti-apoptosis, cell survival and viral genome maintainence, effective inhibition of COX-2 via well-characterized clinically approved COX-2 inhibitors could potentially be used in treatment to control latent KSHV infection and ameliorate KS.
Highlights
Kaposi’s Sarcoma Associated Herpes Virus (KSHV), the most recently discovered human tumor virus, is etiologically associated with Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1,2]
KS lesions are characterized by proliferating spindle shaped endothelial cells, neo-vascular structures, inflammatory cells, and an abundance of inflammatory cytokines (ICs), growth factors (GFs), angiogenic factors and invasive factors such as basic and acidic fibroblast growth factor, interleukin-1a and b (IL-1a and -1b), granulocyte-monocyte colony stimulating factor (GM-CSF), platelet derived growth factor b (PDGF-b), vascular endothelial growth factor (VEGF), interferon-c (IFNc), interlukin 6 (IL-6), tumor necrosis factor a (TNF-a) [2], angiopoietin-2 (Ang2) [5], angiogenin [6], heme oxygenase-1 (HO-1) [7], transforming growth factor b (TGF-b) [8], adhesion molecules like inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1), and matrix metalloproteinases (MMPs) like MMP-1, -2, -3, -9, and -19
We showed that KSHV modulates host factors COX-2/PGE2 for its own advantage to promote its latent infection
Summary
KSHV, the most recently discovered human tumor virus, is etiologically associated with Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1,2]. KS lesions are characterized by proliferating spindle shaped endothelial cells, neo-vascular structures, inflammatory cells, and an abundance of inflammatory cytokines (ICs), growth factors (GFs), angiogenic factors and invasive factors such as basic and acidic fibroblast growth factor (bFGF, aFGF), interleukin-1a and b (IL-1a and -1b), granulocyte-monocyte colony stimulating factor (GM-CSF), platelet derived growth factor b (PDGF-b), vascular endothelial growth factor (VEGF), interferon-c (IFNc), interlukin 6 (IL-6), tumor necrosis factor a (TNF-a) [2], angiopoietin-2 (Ang2) [5], angiogenin [6], heme oxygenase-1 (HO-1) [7], transforming growth factor b (TGF-b) [8], adhesion molecules like inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1), and matrix metalloproteinases (MMPs) like MMP-1, -2, -3, -9, and -19. Cell cultures composed of characteristic spindle-shaped tumor cells have been established from KS lesion explants by the addition of cytokines like TNF-a, TNF-b, IFN-c, IL-1, IL-6, GM-CSF and oncostatin M [1,2,9,10] highlighting the role of these paracrine factors in KS lesion cell survival. A crucial step in KS progression is its striking neovascularization and angiogenesis, which is regulated by aberrant production of angiogenic and anti-angiogenic factors from the infected host cells, uninfected neighboring cells or both
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