title: The novel H2S donor 4-carboxy-phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium.
abstract: Hydrogen sulfide (H2S) 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+2]i), a critical step in mast cell degranulation. The aim of this study was to investigate the role of H2S in [Ca+2]i-dependent mast cell activation.
  
  
  
  We investigated the effects of H2S, either endogenously produced or released by the slow H2S 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+2]iand phosphorylation of proteins downstream of FcεRI activation.
  
  
  
  Endogenously produced H2S inhibited antigen-induced degranulation in RBL-2H3. Similarly, H2S 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+2]ielicited by Ca+2ionophore, 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, H2S diminishes [Ca+2]iavailability 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.
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065, USA.|Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Marino
authors.affiliation: Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.affiliation: Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Citi
authors.affiliation: Cardiovascular and Metabolic Research Unit, Laurentian University, ON, P3E 2C6, Canada.
authors.forename: Ming
authors.initials: M
authors.lastname: Fu
authors.affiliation: Cardiovascular and Metabolic Research Unit, Laurentian University, ON, P3E 2C6, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065, USA. rlevi@med.cornell.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Levi
mesh_terms: D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D015550:Cell Degranulation / Q000187:drug effects*; D006862:Hydrogen Sulfide / Q000737:chemistry / Q000494:pharmacology*; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D012083:Renin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D001565:Benzoates; D017879:Isothiocyanates; C035320:4-isothiocyanatobenzoic acid; D012083:Renin; D002118:Calcium; D006862:Hydrogen Sulfide