The novel H S donor 4-carboxy-phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium.
(2016) British Journal of Pharmacology — Vol. 173, n° 22, p. 3222-3234 (2016)
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- Hydrogen sulfide (H S) modulates many pathophysiological processes, including inflammation and allergic reactions, in which mast cells act as major effector cells. IgE receptor (FcεRI) cross linking leads to an increase in intracellular calcium ([Ca ] ), a critical step in mast cell degranulation. The aim of this study was to investigate the role of H S in [Ca ] -dependent mast cell activation. We investigated the effects of H S, either endogenously produced or released by the slow H S donor 4-carboxy-phenyl isothiocyanate (PhNCS-COOH), on antigenic- and non-antigenic degranulation of native murine mast cells, and human and rat (RBL-2H3) mast cell lines. We measured the release of specific mast cell degranulation markers (β-hexosaminidase and renin), as well as changes in [Ca ] and phosphorylation of proteins downstream of FcεRI activation. Endogenously produced H S inhibited antigen-induced degranulation in RBL-2H3. Similarly, H S released by PhNCS-COOH (10-300 μM) reduced, in a concentration-dependent manner, antigenic and non-antigenic degranulation and renin release in all mast cell types. Notably, PhNCS-COOH also prevented in a concentration-dependent mode the increase in [Ca ] elicited by Ca ionophore, thapsigargin and FcεRI activation. Moreover, PhNCS-COOH attenuated the phosphorylation of Syk, cPLA-2 and PLCγ1 in antigen-stimulated RBL-2H3 cells. Collectively, our results demonstrate that, by attenuating the phosphorylation of proteins downstream of FcεRI cross-linking on mast cells, H S diminishes [Ca ] availability and thus mast cell degranulation and renin release. These findings suggest that PhNCS-COOH could be a strategic therapeutic tool in mast cell-mediated allergic conditions.
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Marino, A., Martelli, A., Citi, V., Fu, M., Wang, R., Calderone, V., & Levi, R. (2016). The novel H S donor 4-carboxy-phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium. British Journal of Pharmacology, 173(22), 3222-3234. https://doi.org/10.1111/bph.13583 (Original work published 2016)