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National Institute of Environmental Health Sciences

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Publication Detail

Title: Monomethylarsonous acid (MMA+3) Inhibits IL-7 Signaling in Mouse Pre-B Cells.

Authors: Ezeh, Peace C; Xu, Huan; Lauer, Fredine T; Liu, Ke Jian; Hudson, Laurie G; Burchiel, Scott W

Published In Toxicol Sci, (2016 Feb)

Abstract: Our previously published data show that As(+3) in vivo and in vitro, at very low concentrations, inhibits lymphoid, but not myeloid stem cell development in mouse bone marrow. We also showed that the As(+3) metabolite, monomethylarsonous acid (MMA(+3)), was responsible for the observed pre-B cell toxicity caused by As(+3). Interleukin-7 (IL-7) is the primary growth factor responsible for pre-lymphoid development in mouse and human bone marrow, and Signal Transducer and Activator of Transcription 5 (STAT5) is a transcriptional factor in the IL-7 signaling pathway. We found that MMA(+3) inhibited STAT5 phosphorylation at a concentration as low as 50 nM in mouse bone marrow pre-B cells. Inhibition of STAT5 phosphorylation by As(+3) occurred only at a concentration of 500 nM. In the IL-7 dependent mouse pre-B 2E8 cell line, we also found selective inhibition of STAT5 phosphorylation by MMA(+3), and this inhibition was dependent on effects on JAK3 phosphorylation. IL-7 receptor expression on 2E8 cell surface was also suppressed by 50 nM MMA(+3) at 18 h. As further evidence for the inhibition of STAT5, we found that the induction of several genes required in B cell development, cyclin D1, E2A, EBF1, and PAX5, were selectively inhibited by MMA(+3). Since 2E8 cells lack the enzymes responsible for the conversion of As(+3) to MMA(+3) in vitro, the results of these studies suggest that As(+3) induced inhibition of pre-B cell formation in vivo is likely dependent on the formation of MMA(+3) which in turn inhibits IL-7 signaling at several steps in mouse pre-B cells.

PubMed ID: 26518055 Exiting the NIEHS site

MeSH Terms: Animals; Arsenic/toxicity; Interleukin-7/antagonists & inhibitors*; Interleukin-7/physiology; Janus Kinase 1/antagonists & inhibitors; Male; Mice; Mice, Inbred C57BL; Organometallic Compounds/toxicity*; Phosphorylation; Precursor Cells, B-Lymphoid/drug effects*; Precursor Cells, B-Lymphoid/immunology; Precursor Cells, B-Lymphoid/physiology; STAT5 Transcription Factor/antagonists & inhibitors; STAT5 Transcription Factor/metabolism; Signal Transduction/drug effects*

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