Piracy of prostaglandin E2/EP receptor-mediated signaling by Kaposi's sarcoma-associated herpes virus (HHV-8) for latency gene expression: strategy of a successful pathogen.
Kaposi's sarcoma-associated herpes virus (KSHV) is implicated in the pathogenesis of KS, a chronic inflammation-associated malignancy. Cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2), two pivotal proinflammatory/oncogeneic molecules, are proposed to play roles in the expression of major KSHV latency-associated nuclear antigen-1 (LANA-1). Microsomal PGE2 synthase, PGE2, and its receptors (EP1, EP2, EP3, and EP4) were detected in KS lesions with the distinct staining of EP2/EP4 in KS lesions. In latently infected endothelial TIVE-LTC cells, EP receptor antagonists downregulated LANA-1 expression as well as Ca(2+), p-Src, p-PI3K, p-PKCzeta/lambda, and p-NF-kappaB, which are also some of the signal molecules proposed to be important in KS pathogenesis. Exogenous PGE2 and EP receptor agonists induced the LANA-1 promoter in 293 cells, and YY1, Sp1, Oct-1, Oct-6, C/EBP, and c-Jun transcription factors seem to be involved in this induction. PGE2/EP receptor-induced LANA-1 promoter activity was downregulated significantly by the inhibition of Ca(2+), p-Src, p-PI3K, p-PKCzeta/lambda, and p-NF-kappaB. These findings implicate the inflammatory PGE2/EP receptors and the associated signal molecules in herpes virus latency and uncover a novel paradigm that shows the evolution of KSHV genome plasticity to use inflammatory response for its survival advantage of maintaining latent gene expression. These data also suggest that potential use of anti-COX-2 and anti-EP receptor therapy may not only ameliorate the chronic inflammation associated with KS but could also lead to elimination of the KSHV latent infection and the associated KS lesions.
George Paul
Arun
A
HM Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
Sharma-Walia
Neelam
N
Kerur
Nagaraj
N
White
Carl
C
Chandran
Bala
B
D000956:Antigens, Viral / Q000096:biosynthesis / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000821:virology; D015870:Gene Expression; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D015854:Up-Regulation; D017735:Virus Latency; D019061:src-Family Kinases / Q000378:metabolism
D000956:Antigens, Viral; D016328:NF-kappa B; D009687:Nuclear Proteins; D018078:Receptors, Prostaglandin E; C109540:latency-associated nuclear antigen; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D011493:Protein Kinase C; D015232:Dinoprostone; D002118:Calcium
J Virol. 2005 Nov;79(22):14457-64
16254382
J Biol Chem. 2001 Oct 19;276(42):38658-64
11509575
Panminerva Med. 2007 Sep;49(3):119-38
17912148
Virology. 2004 Oct 10;328(1):7-18
15380353
J Virol. 2006 May;80(10):4833-46
16641275
Immunol Rev. 1992 Jun;127:147-55
1506004
Gut. 2006 Jan;55(1):115-22
16118353
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5704-9
10318948
Blood. 1999 Jun 15;93(12):4034-43
10361100
Virology. 2006 Jun 20;350(1):192-205
16616289
J Virol. 2004 Apr;78(8):4207-23
15047836
Prostaglandins. 1980 Jun;19(6):917-31
7384560
Science. 2005 Dec 2;310(5753):1504-10
16293724
Genome Biol. 2004;5(9):241
15345041
Clin Microbiol Rev. 2002 Jul;15(3):439-64
12097251
J Virol. 2003 Jan;77(2):1524-39
12502866
Prostaglandins Other Lipid Mediat. 2006 Dec;81(3-4):150-61
17085323
Annu Rev Pathol. 2006;1:273-96
18039116
Cancer Res. 2006 Oct 15;66(20):9794-7
17047037
J Virol. 1999 Feb;73(2):1438-46
9882349
Lung Cancer. 2002 Apr;36(1):33-42
11891031
Mol Cancer Res. 2008 Jun;6(6):1003-16
18567804
PLoS Pathog. 2010 Feb 12;6(2):e1000777
20169190
J Biol Chem. 2007 Apr 20;282(16):11613-7
17329241
Blood. 2001 Apr 15;97(8):2374-80
11290600
J Biol Chem. 2001 Mar 9;276(10):7122-8
11116138
Trends Pharmacol Sci. 2003 Oct;24(10):524-9
14559404
J Virol. 2007 Apr;81(8):3949-68
17287275
Arch Virol. 2003 May;148(5):871-90
12721796
J Virol. 2004 Apr;78(7):3601-20
15016882
J Virol. 2008 Feb;82(4):1759-76
18057235
Mol Cell Biol. 2000 Jun;20(12):4265-74
10825190
J Virol. 2006 Jul;80(13):6534-52
16775340
J Virol. 2009 Apr;83(7):3342-64
19158252
Cancer Res. 2004 Jan 1;64(1):72-84
14729610