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Bidirectional counter-regulation of human lung mast cell and airway smooth muscle beta2-adrenoceptors

journal contribution
posted on 03.11.2015, 09:52 by Rebecca J. Lewis, Latifa Chachi, Chris Newby, Yassine Amrani, Peter Bradding
Human lung mast cells (HLMCs) play a central role in asthma pathogenesis through their relocation to the airway smooth muscle (ASM) bundles. β2 adrenoceptor (β2-AR)-agonists are used to relieve bronchoconstriction in asthma, but may reduce asthma control, particularly when used as monotherapy. We hypothesized that HLMC and human ASM cell (HASMC) responsiveness to β2-AR agonists would be attenuated when HLMCs are in contact with HASMCs. Cells were cultured in the presence of the short-acting β2-agonist albuterol, and the long-acting β2-agonists formoterol and olodaterol. Constitutive and FcεRI-dependent HLMC histamine release, HASMC contraction, and β2-AR phosphorylation at Tyr(350) were assessed. Constitutive HLMC histamine release was increased in HLMC-HASMC coculture and this was enhanced by β2-AR agonists. Inhibition of FcεRI-dependent HLMC mediator release by β2-agonists was greatly reduced in HLMC-HASMC coculture. These effects were reversed by neutralization of stem cell factor (SCF) or cell adhesion molecule 1 (CADM1). β2-AR agonists did not prevent HASMC contraction when HLMCs were present, but this was reversed by fluticasone. β2-AR phosphorylation at Tyr(350) occurred within 5 min in both HLMCs and HASMCs when the cells were cocultured, and was inhibited by neutralizing SCF or CADM1. HLMC interactions with HASMCs via CADM1 and Kit inhibit the potentially beneficial effects of β2-AR agonists on these cells via phosphorylation of the β2-AR. These results may explain the potentially adverse effects of β2-ARs agonists when used for asthma therapy. Targeting SCF and CADM1 may enhance β2-AR efficacy, particularly in corticosteroid-resistant patients.

History

Citation

Journal of Immunology, 2016, 196 (1), pp. 55-63

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation

Version

AM (Accepted Manuscript)

Published in

Journal of Immunology

issn

0022-1767

eissn

1550-6606

Acceptance date

30/10/2015

Copyright date

2015

Publisher version

http://www.jimmunol.org/content/196/1/55

Notes

The file associated with this record is under a permanent embargo in accordance with the publisher's policy regarding depositing in institutional repositories. The full text may be available through the publisher links above.

Language

en

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