Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

Abstract

Background and PurposeAlthough 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.Experimental approachWe 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.Key resultsCDMCs 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 and ImplicationsWe 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.

The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells

“…38 A recent publication also reported that cromolyn inhibited PGD 2 release from hCBMC stimulated by IgE/Anti-IgE by 100%. 42 It is, therefore apparent that cromolyn can inhibit the release of histamine and arachidonic acid products, but not cytokines, whether due to IgE/anti-IgE or SP stimulation. In contrast, lut and methlut are more effective MC inhibitors than cromolyn regardless of the trigger and the mediator measured.…”

Characterization of a Secretory Annexin in Echinococcus granulosus

“…17 Interestingly, some annexins without any secretory signals have been found in the extracellular space (e.g., annexin A1, A2, and A5 of human and annexin B1 of T. solium). 15,[18][19][20] The mechanism by which this occurs remains unclear and is worthy of investigation. 15,21 Recently, proteomic research on E. granulosus has shown that annexin B33 protein (Eg-ANX) could be detected in the excreted/secreted (ES) product and hydatid cyst fluid, which might potentially play important roles in parasite survival mechanisms during infection.…”

The resolution of acute inflammation induced by cyclic AMP is dependent on annexin A1

“…Originally described as an endogenous mediator of the anti-inflammatory effects of glucocorticoids, over the past 20 years, AnxA1 has been shown to have a broad range of molecular and cellular actions, including modulation of leukocyte migration in acute and chronic inflammation, kinase activities in signal transduction, preservation of cytoskeleton and extracellular matrix integrity, tissue maintenance, apoptosis, cell growth, and differentiation (1)(2)(3)(4)(5). AnxA1 is particularly abundant in cells of the myeloid lineage, including neutrophils, eosinophils, macrophages, and mast cells (6). In resting cells, AnxA1 is by and large localized in the cytosol, and upon activation, it can be secreted and then resynthesized.…”