title: Environmentally relevant concentrations of arsenite and monomethylarsonous acid inhibit IL-7/STAT5 cytokine signaling pathways in mouse CD3+CD4-CD8- double negative thymus cells.
abstract: Environmental arsenic exposure is a public health issue. Immunotoxicity induced by arsenic has been reported in humans and animal models. The purpose of this study was to evaluate mechanisms of As(+3) and MMA(+3) toxicity in mouse thymus cells. Because we know that MMA(+3) inhibits IL-7 signaling in mouse bone marrow pre-B cells, we studied the influence of As(+3) and MMA(+3) on T cell development in the thymus at the earliest stage of T cell development (CD4-CD8-, double negative, DN) which requires IL-7 dependent signaling. We found in a DN thymus cell line (D1) that a low concentration of MMA(+3) (50 nM) suppressed IL-7 dependent JAK1, 3 and STAT5 signaling. As(+3) suppressed STAT5 and JAK3 at higher concentrations (500 nM). Cell surface expression of the IL-7 receptor (CD127) was also suppressed by 50 nM MMA(+)3, but was increased by 500 NM As(+3), indicating possible differences in the mechanisms of action of these agents. A decrease in cyclin D1 protein expression was observed in D1 cells exposed to As(+3) at 500 nM and MMA(+3) starting at 50 nM, suggesting that arsenic at these environmentally-relevant doses suppresses early T cell development through the inhibition of IL-7 signaling pathway.
authors.affiliation: The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque NM 87131, United States.
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.affiliation: The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque NM 87131, United States.
authors.forename: Fredine T
authors.initials: FT
authors.lastname: Lauer
authors.affiliation: The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque NM 87131, United States.
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
authors.affiliation: The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque NM 87131, United States.
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
authors.affiliation: The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque NM 87131, United States. Electronic address: sburchiel@salud.unm.edu.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Burchiel
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000633:toxicity*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects*
chemical_list: D018053:Arsenites; C530105:Ccnd1 protein, mouse; D015851:Interleukin-7; D009942:Organometallic Compounds; D050799:STAT5 Transcription Factor; C406082:monomethylarsonous acid; D019938:Cyclin D1; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3
keywords: Arsenite; Cyclin D1; Double negative T cells; IL-7 signaling; JAK/STAT; Monomethylarsonous acid; Selective toxicity