title: Arsenic inhibits mast cell degranulation via suppression of early tyrosine phosphorylation events.
abstract: Exposure to arsenic is a global health concern. We previously documented an inhibitory effect of inorganic Arsenite on IgE-mediated degranulation of RBL-2H3 mast cells (Hutchinson et al., 2011; J. Appl. Toxicol. 31: 231-241). Mast cells are tissue-resident cells that are positioned at the host-environment interface, thereby serving vital roles in many physiological processes and disease states, in addition to their well-known roles in allergy and asthma. Upon activation, mast cells secrete several mediators from cytoplasmic granules, in degranulation. The present study is an investigation of Arsenite's molecular target(s) in the degranulation pathway. Here, we report that arsenic does not affect degranulation stimulated by either the Ca(2) (+) ionophore A23187 or thapsigargin, which both bypass early signaling events. Arsenic also does not alter degranulation initiated by another non-IgE-mediated mast cell stimulant, the G-protein activator compound 48/80. However, arsenic inhibits Ca(2) (+) influx into antigen-activated mast cells. These results indicate that the target of arsenic in the degranulation pathway is upstream of the Ca(2) (+) influx. Phospho-Syk and phospho-p85 phosphoinositide 3-kinase enzyme-linked immunosorbent assays data show that arsenic inhibits early phosphorylation events. Taken together, this evidence indicates that the mechanism underlying arsenic inhibition of mast cell degranulation occurs at the early tyrosine phosphorylation steps in the degranulation pathway. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, 04469, USA.
authors.forename: Juyoung
authors.initials: J
authors.lastname: Shim
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, 04469, USA.|Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, 04469, USA.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Kennedy
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, 04469, USA.|Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, 04469, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Weatherly
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, 04469, USA.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Hutchinson
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, 04469, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Pelletier
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, 04469, USA.
authors.forename: Hina N
authors.initials: HN
authors.lastname: Hashmi
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, 04469, USA.
authors.forename: Kayla
authors.initials: K
authors.lastname: Blais
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, 04469, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Velez
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, 04469, USA. Julie.gosse@maine.edu.|Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, 04469, USA. Julie.gosse@maine.edu.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Gosse
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D015550:Cell Degranulation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D000072377:Syk Kinase / Q000037:antagonists & inhibitors
chemical_list: D018053:Arsenites; D004785:Environmental Pollutants; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat; D002118:Calcium
keywords: Syk; arsenic; calcium; degranulation; mast cell; phosphoinositide 3-kinase