title: Monomethylarsonous acid (MMA+3) Inhibits IL-7 Signaling in Mouse Pre-B Cells.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, 87131-0001.
authors.forename: Peace C
authors.initials: PC
authors.lastname: Ezeh
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, 87131-0001.
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, 87131-0001.
authors.forename: Fredine T
authors.initials: FT
authors.lastname: Lauer
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, 87131-0001.
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, 87131-0001.
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, 87131-0001 sburchiel@salud.unm.edu.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Burchiel
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity; D015851:Interleukin-7 / Q000037:antagonists & inhibitors* / Q000502:physiology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000633:toxicity*; D010766:Phosphorylation; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015851:Interleukin-7; D009942:Organometallic Compounds; D050799:STAT5 Transcription Factor; C576410:interleukin-7, mouse; C406082:monomethylarsonous acid; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D001151:Arsenic
keywords: Arsenite; STAT5; lymphoid progenitors; monomethylarsonous acid; mouse pre-B cells; selective toxicity