title: Anti-allergic cromones inhibit histamine and eicosanoid release from activated human and murine mast cells by releasing Annexin A1.
abstract: OBJECTIVE
  Although the 'cromones' (di-sodium cromoglycate and sodium nedocromil) are used to treat allergy and asthma, their 'mast cell stabilising' mechanism of pharmacological action has never been convincingly explained. Here, we investigate the hypothesis that these drugs act by stimulating the release of the anti-inflammatory protein Annexin-A1 (Anx-A1) from mast cells.
  
  
  METHODS
  We used biochemical and immuno-neutralisation techniques to investigate the mechanism by which cromones suppress histamine and eicosanoid release from cord-derived human mast cells (CDMCs) or murine bone marrow-derived mast cells (BMDMCs) from wild type and Anx-A1 null mice.
  
  
  RESULTS
  CDMCs activated by IgE-FcRε1 crosslinking, released histamine and prostaglandin (PG) D2, which were inhibited (30-65%) by 5 min pre-treatment with cromoglycate (10 nM) or nedocromil (10 nM), as well as dexamethasone (2 nM) and human recombinant Anx-A1 (1-10 nM). In CDMCs cromones potentiated (2-5 fold) protein kinase C (PKC) phosphorylation and Anx-A1 phosphorylation and secretion (3-5 fold). Incubation of CDMCs with a neutralising anti-Anx-A1 monoclonal antibody reversed the cromone inhibitory effect. Nedocromil (10 nM) also inhibited (40-60%) the release of mediators from murine bone marrow derived-mast cells from wild type mice activated by compound 48/80 and IgE-FcRε1 cross-linking, but were inactive in such cells when these were prepared from Anx-A1 null mice or when the neutralising anti-Anx-A1 antibody was present.
  
  
  CONCLUSIONS
  We conclude that stimulation of phosphorylation and secretion of Anx-A1 is an important component of inhibitory cromone actions on mast cells, which could explain their acute pharmacological actions in allergy. These findings also highlight a new pathway for reducing mediator release from these cells.
authors.affiliation: Division of Molecular Therapy, Institute of Ophthalmology, London, United Kingdom. s.yazid@ucl.ac.uk
authors.forename: Samia
authors.initials: S
authors.lastname: Yazid
authors.forename: Ajantha
authors.initials: A
authors.lastname: Sinniah
authors.forename: Egle
authors.initials: E
authors.lastname: Solito
authors.forename: Virginia
authors.initials: V
authors.lastname: Calder
authors.forename: Rod J
authors.initials: RJ
authors.lastname: Flower
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018926:Anti-Allergic Agents / Q000494:pharmacology; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D002478:Cells, Cultured; D004205:Cromolyn Sodium / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D015777:Eicosanoids / Q000378:metabolism*; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017835:Nedocromil / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000378:metabolism; D011994:Recombinant Proteins
chemical_list: D017305:Annexin A1; D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; D000888:Antibodies, Anti-Idiotypic; D015777:Eicosanoids; D011994:Recombinant Proteins; D017835:Nedocromil; D007073:Immunoglobulin E; D003907:Dexamethasone; D004205:Cromolyn Sodium; D015230:Prostaglandin D2