title: Aryl hydrocarbon receptor-mediated induction of EBV reactivation as a risk factor for Sjögren's syndrome.
abstract: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a variety of biological effects by binding to environmental pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin). Although numerous animal studies have demonstrated the harmful effects of dioxins, it remains controversial whether dioxins pose a risk to human health. Enhanced lytic replication of EBV is a risk factor for the development of autoimmune diseases and cancers. This study evaluated the possibility that ligand-activated AhR reactivates EBV. EBV reactivation and AhR transactivation were evaluated with luciferase assays. Saliva samples were collected from 19 patients with primary Sjögren's syndrome (SS). Control saliva samples were obtained from 10 healthy individuals and nine patients with severe dry mouth. TCDD enhanced BZLF1 transcription, which mediates the switch from the latent to the lytic form of EBV infection in EBV-positive B cell lines and in a salivary gland epithelial cell line. Moreover, TCDD-induced increases in BZLF1 mRNA and EBV genomic DNA levels were confirmed in the B cell lines. Saliva from SS patients activated the transcription of both CYP1A1 and BZLF1. Additionally, there was a positive correlation between CYP1A1 and BZLF1 promoter activities. AhR ligands elicited the reactivation of EBV in activated B cells and salivary epithelial cells, and these ligands are involved in SS. Our findings reveal novel aspects of the biological effects of dioxin and the AhR-dependent pathogenesis of autoimmune diseases.
authors.affiliation: Department of Pathology, Tsurumi University School of Dental Medicine, Kanagawa 230-8501, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Inoue
authors.forename: Kenji
authors.initials: K
authors.lastname: Mishima
authors.forename: Sachi
authors.initials: S
authors.lastname: Yamamoto-Yoshida
authors.forename: Ryoko
authors.initials: R
authors.lastname: Ushikoshi-Nakayama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Kofuchi
authors.initials: K
authors.lastname: Ryo
authors.forename: Fumio
authors.initials: F
authors.lastname: Ide
authors.forename: Ichiro
authors.initials: I
authors.lastname: Saito
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002144:Callithrix; D002461:Cell Line, Transformed; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000276:immunology; D004785:Environmental Pollutants / Q000009:adverse effects / Q000494:pharmacology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000276:immunology; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D000072317:Polychlorinated Dibenzodioxins / Q000009:adverse effects / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology* / Q000378:metabolism; D012307:Risk Factors; D012469:Salivary Glands / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015534:Trans-Activators / Q000096:biosynthesis / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D014775:Virus Activation / Q000187:drug effects / Q000276:immunology*
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D015534:Trans-Activators; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1