title: Glucocorticoids activate Epstein Barr virus lytic replication through the upregulation of immediate early BZLF1 gene expression.
abstract: Psychological stress-associated immune dysregulation has been shown to disrupt the steady-state expression and reactivate latent herpes viruses. One such virus is the Epstein Barr virus (EBV), which is associated with several human malignancies. EBV infects >90% of people living in North America and persists for life in latently infected cells. Although several studies have shown that glucocorticoids (GCs) can directly induce reactivation of the latent virus, the mechanism of stress hormone involvement in the control of EBV gene expression is not well understood. In this study, we tested the hypothesis that GCs can induce the latent EBV genome to lytically replicate through the induction of the EBV immediate early gene BZLF1 which encodes the lytic transactivator protein ZEBRA. We show a dose-dependent upregulation of BZLF1 mRNA expression by hydrocortisone (HC) and dexamethasone (Dex) in Daudi cells, an EBV genome positive Burkitt's lymphoma cell line, and Dex-induction of the early gene products BLLF3 (encoding for the EBV dUTPase) and BALF5 (encoding for the EBV DNA polymerase). We show that Daudi cells express glucocorticoid receptors (GR) that mediate Dex-dependent upregulation of BZLF1 mRNA levels. This effect was inhibited by both the glucocorticoid receptor antagonist RU486 and by cycloheximide. The results suggest that GCs, in addition to inducing stress-related immune dysregulation, can mediate latent EBV reactivation through the induction of the BZLF1 gene.
authors.affiliation: Institute for Behavioral Medicine Research, The Ohio State University Medical Center, 460 Medical Center Drive, Columbus, OH 43210, USA.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Yang
authors.forename: Jeanette I
authors.initials: JI
authors.lastname: Webster Marketon
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Kwok Wai
authors.initials: KW
authors.lastname: Lo
authors.forename: Seung-jae
authors.initials: SJ
authors.lastname: Kim
authors.forename: Ronald
authors.initials: R
authors.lastname: Glaser
mesh_terms: D015153:Blotting, Western; D002051:Burkitt Lymphoma; D002460:Cell Line; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000235:genetics*; D005938:Glucocorticoids / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011755:Pyrophosphatases / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D006727:Hormone Antagonists; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D014764:Viral Proteins; D015735:Mifepristone; D003907:Dexamethasone; D003513:Cycloheximide; C083202:BALF5 protein, Epstein-barr virus; D004259:DNA-Directed DNA Polymerase; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase
references.citation: Int J Cancer. 1999 Sep 24;83(1):121-6
references.pmid: 10449618
references.citation: Virus Res. 1989 Jan;12(1):53-9
references.pmid: 2541582
references.citation: Eval Health Prof. 2000 Sep;23(3):243-63
references.pmid: 11067190
references.citation: J Gravit Physiol. 2007 Jul;14(1):P21-5
references.pmid: 18372687
references.citation: Brain Behav Immun. 1991 Jun;5(2):219-32
references.pmid: 1654167
references.citation: Arch Virol. 1999;144(11):2219-27
references.pmid: 10603176
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Mol Endocrinol. 1993 Jan;7(1):12-6
references.pmid: 8446102
references.citation: J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):11-21
references.pmid: 17070034
references.citation: Mol Endocrinol. 1991 Feb;5(2):267-72
references.pmid: 1645455
references.citation: Proc Natl Acad Sci U S A. 1989 Dec;86(23):9524-8
references.pmid: 2556716
references.citation: J Psychosom Res. 1994 Jan;38(1):63-78
references.pmid: 8126691
references.citation: J Clin Microbiol. 1999 Jan;37(1):132-6
references.pmid: 9854077
references.citation: Neuroendocrinology. 1995 Oct;62(4):356-61
references.pmid: 8544949
references.citation: J Med Virol. 2000 Jun;61(2):235-40
references.pmid: 10797380
references.citation: Brain Behav Immun. 2005 May;19(3):235-42
references.pmid: 15797312
references.citation: Virology. 1988 Feb;162(2):503-7
references.pmid: 2829433
references.citation: J Virol. 2007 Sep;81(17):9279-91
references.pmid: 17596302
references.citation: Aviat Space Environ Med. 1999 Dec;70(12):1211-3
references.pmid: 10596777
references.citation: Science. 1972 Jun 16;176(4040):1245-7
references.pmid: 4338252
references.citation: Acta Virol. 1981 May;25(3):163-6
references.pmid: 6115566
references.citation: J Med Virol. 2001 Jun;64(2):149-56
references.pmid: 11360247
references.citation: Horm Behav. 2002 Aug;42(1):32-41
references.pmid: 12191645
references.citation: J Virol. 1990 May;64(5):1984-90
references.pmid: 2157866
references.citation: Cancer Res. 1973 Sep;33(9):2142-8
references.pmid: 4353485
references.citation: Brain Behav Immun. 1987 Mar;1(1):7-20
references.pmid: 2837297
references.citation: Endocrinology. 1984 Jul;115(1):25-32
references.pmid: 6329650
references.citation: Nat Rev Immunol. 2005 Mar;5(3):243-51
references.pmid: 15738954
references.citation: Ann Intern Med. 1995 Jul 15;123(2):81-8
references.pmid: 7778839
references.citation: Proc Natl Acad Sci U S A. 1982 Mar;79(6):2036-40
references.pmid: 6952251
references.citation: J Clin Microbiol. 1990 Jun;28(6):1403-10
references.pmid: 2166084
references.citation: Psychosom Med. 1992 May-Jun;54(3):354-71
references.pmid: 1320279
references.citation: Neuroimmunomodulation. 2000;8(2):51-8
references.pmid: 10965229
references.citation: Trends Microbiol. 1997 Oct;5(10):399-405
references.pmid: 9351176
references.citation: Int J Cancer. 1983 Mar 15;31(3):291-5
references.pmid: 6826253
references.citation: Virology. 1979 Sep;97(2):477-81
references.pmid: 224594
references.citation: Psychoneuroendocrinology. 1994;19(8):765-72
references.pmid: 7991763
references.citation: Brain Behav Immun. 2005 Mar;19(2):91-103
references.pmid: 15664781
references.citation: Rev Can Biol. 1974 Jun;33(2):135-47
references.pmid: 4369295
references.citation: Health Psychol. 1993 Nov;12(6):435-42
references.pmid: 8293726