Abstract
IntroductionChronic mast cell activation is a characteristic feature of asthma. BEAS-2B human airway epithelial cells (AEC) profoundly inhibit both constitutive and IgE-dependent human lung mast cell (HLMC) histamine release. The aim of this study was to examine the regulation of HLMC degranulation by primary AEC from healthy and asthmatic subjects, and investigate further the inhibitory mechanism.MethodsHLMC were co-cultured with both BEAS-2B and primary AEC grown as monolayers or air-liquid interface (ALI) cultures.ResultsBoth constitutive and IgE-dependent HLMC histamine release were attenuated by BEAS-2B, primary AEC monolayers and ALI cultures. This occurred in the absence of HLMC-AEC contact indicating the presence of a soluble factor. Unlike healthy ALI AEC, asthmatic ALI-AEC did not significantly reduce constitutive histamine release. AEC inhibitory activity was transferable in primary AEC monolayer supernatant, but less active than with Transwell co-culture, suggesting that the inhibitory factor was labile. The AEC inhibitory effects were attenuated by both AEC wounding and pertussis toxin, indicating the involvement of a G0/Gi receptor coupled mechanism. Solid phase extraction of lipids (<10 kDa) removed the AEC inhibitory activity. The lipid derivatives resolvin D1 and D2 and lipoxin A4 attenuated HLMC histamine release in a dose-dependent fashion but were not detectable in co-culture supernatants.ConclusionsPrimary AEC suppress HLMC constitutive and IgE-dependent histamine secretion through the release of a soluble, labile lipid mediator(s) that signals through the G0/Gi receptor coupled mechanism. Manipulation of this interaction may have a significant therapeutic role in asthma.
Highlights
Chronic mast cell activation is a characteristic feature of asthma
Since the airway epithelium in asthma is denuded and expresses an inflammatory phenotype with impaired repair responses [15], we proposed the following hypothesis: that the role of the healthy intact epithelium is to keep mast cells in a quiescent state, and that tissue insults such as those caused by infection or that present in asthma lead to epithelial damage and denudation which leads to the loss of this bronchoprotective function
We extended our original work examining the suppression of human lung mast cell (HLMC) degranulation in direct contact with confluent BEAS-2B cells, by comparing the co-culture of HLMC and BEAS-2B cells separated by a 0.40 mm Transwell membrane (BEAS-2B on the underside, HLMC in the top chamber)
Summary
BEAS-2B human airway epithelial cells (AEC) profoundly inhibit both constitutive and IgE-dependent human lung mast cell (HLMC) histamine release. There is ongoing production and release of mast cell-derived autacoid mediators and cytokines [3] and morphological evidence of degranulation within asthmatic airways [4] Mast cells infiltrate three key structures in asthma: the airway epithelium [5], the airway submucosal glands [6], and the airway smooth muscle [7]. Recent work has highlighted important bi-directional interactions between human lung mast cells (HLMC) and airway smooth muscle, including the ability of ASM to increase constitutive mast cell degranulation [8;9]. These interactions are likely to promote ASM dysfunction in asthma. AEC activated with various stimuli produce TSLP which may induce IL-13 release from cultured mast cells derived from peripheral blood progenitors [12], and mast cells are required for epithelial TSLP expression in a model of allergic rhinitis [13]
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