Arsenic inhibits mast cell degranulation via suppression of early tyrosine phosphorylation events

作者：Shim Juyoung; Kennedy Rachel H; Weatherly Lisa M; Hutchinson Lee M; Pelletier Jonathan H; Hashmi Hina N; Blais Kayla; Velez Alejandro; Gosse Julie A^*

来源：Journal of Applied Toxicology, 2016, 36(11): 1446-1459.

DOI：10.1002/jat.3300

• arsenic
• mast cell
• degranulation
• calcium
• Syk
• phosphoinositide 3-kinase

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 Ca2+ 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 Ca2+ influx into antigen-activated mast cells. These results indicate that the target of arsenic in the degranulation pathway is upstream of the Ca2+ 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 (c) 2016 John Wiley & Sons, Ltd.
Arsenite inhibits IgE-mediated degranulation of RBL-2H3 mast cells. Mast cells serve vital roles in many physiological processes and diseases. Upon activation, mast cells secrete mediators from cytoplasmic granules, in degranulation. Here, we report that arsenic does not affect degranulation stimulated by Ca2+ ionophore A23187, thapsigargin, or the G-protein activator compound 48/80, all of which bypass early signaling events. However, arsenic inhibits the Ca2+ influx into antigen-activated mast cells. Syk and phosphoinositide 3-kinase enzyme-linked immunosorbent assay data show that arsenic inhibits early phosphorylation events.

• 出版日期2016-11