Environmentally relevant concentrations of arsenite and monomethylarsonous acid inhibit IL-7/STAT5 cytokine signaling pathways in mouse CD3+CD4-CD8- double negative thymus cells. (15th April 2016)

• Record Type: Journal Article
• Authors: Xu, Huan; Lauer, Fredine T.; Liu, Ke Jian; Hudson, Laurie G.; Burchiel, Scott W.
• Is Part Of: Toxicology letters. Volume 247(2016)
• Page Start: 62
• Page End: 68
• Publication Date: 2016-04-15
• Subjects: Arsenite -- Monomethylarsonous acid -- Double negative T cells -- IL-7 signaling -- JAK/STAT -- Cyclin D1 -- Selective toxicity; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2016.02.014
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: As +3 and MMA +3 suppress IL-7 signaling as measured by pSTAT5 in DN thymocytes. JAK1 was inhibited by MMA +3, while JAK3 was inhibited by MMA +3 and As +3 . MMA +3 decreased but As +3 increased cell surface expression of the IL-7 receptors. MMA +3 and As +3 exposures selectively decreased the DN cell population in vitro . In DN cells, MMA +3 (50 nM) and As +3 (500 nM) inhibited cyclin D1 expression. 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.