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.