H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States of America.
PLoS Pathog. 2010 Feb 12;6(2):e1000777. doi: 10.1371/journal.ppat.1000777.
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.
卡波西肉瘤（KS）是一种神秘的内皮细胞血管肿瘤，其特征是梭形内皮细胞的增殖、炎症细胞因子（ICs）、生长因子（GFs）和血管生成因子。KSHV 与 KS 有病因学联系，并在 KS 病变内皮细胞中表达其潜伏基因。人微血管内皮细胞（HMVEC-d）的原发性感染导致潜伏感染的建立和宿主基因的重编程，环氧化酶-2（COX-2）是高度上调的基因之一。我们之前的研究表明 COX-2 在 KSHV 潜伏的建立和维持中起作用。在这里，我们研究了 COX-2 在诱导新感染内皮细胞过程中发生的 ICs、GFs、血管生成和侵袭事件中的作用。KS 组织切片中检测到大量 COX-2。支持 KSHV 稳定潜伏的端粒酶永生化人脐静脉内皮细胞（TIVE-LTC）表达高水平的功能性 COX-2 和微粒体 PGE2 合酶（m-PGES），并分泌主要的花生四烯酸炎症代谢物 PGE2。感染的 HMVEC-d 和 TIVE-LTC 细胞分泌多种 ICs、GFs、血管生成因子和基质金属蛋白酶（MMPs），这些因子通过化学抑制剂或 siRNA 抑制 COX-2 均可显著阻断。这些因子诱导未感染内皮细胞管形成的能力也被抑制。在 KSHV 感染早期分泌的 PGE2 通过激活小 G 蛋白 Rac1，极大地增加了未感染内皮细胞对纤维连接蛋白的粘附。COX-2 抑制显著降低了 TIVE-LTC 细胞中 KSHV 潜伏 ORF73 基因的表达和存活。总的来说，这些研究强调了 KSHV 诱导的 COX-2/PGE2 在新感染过程中创造 KS 病变样微环境中的关键作用。由于 COX-2 在 KSHV 潜伏基因表达中发挥多种作用，而这些基因本身是细胞因子诱导、抗凋亡、细胞存活和病毒基因组维持的有力介质，因此通过经过充分特征描述的临床批准的 COX-2 抑制剂有效抑制 COX-2 可能用于治疗以控制潜伏性 KSHV 感染并改善 KS。
