Environmentally relevant concentrations of arsenite and monomethylarsonous acid inhibit IL-7/STAT5 cytokine signaling pathways in mouse CD3+CD4-CD8- double negative thymus cells

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.