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Protein phosphatase 5 mediates corticosteroid insensitivity in airway smooth muscle in patients with severe asthma.

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journal contribution
posted on 2016-11-03, 11:45 authored by L. Chachi, M. Abbasian, A. Gavrila, A. Alzahrani, O. Tliba, P. Bradding, A. J. Wardlaw, C. Brightling, Y. Amrani
BACKGROUND: The mechanisms driving glucocorticoid (GC) insensitivity in patients with severe asthma are still unknown. Recent evidence suggests the existence of GC-insensitive pathways in airway smooth muscle (ASM) caused by a defect in GC receptor (GRα) function. We examined whether other mechanisms could potentially explain the reduced sensitivity of ASM cells to GC in severe asthmatics. METHODS: Airway smooth muscle cells from healthy and severe asthmatic subjects were treated with TNF-α and responses to corticosteroids in both cohorts were compared by ELISA, immunoblot, immunohistochemistry and real-time PCR. Immunohistochemistry and flow cytometry assays were used to assess the expression of the protein phosphatase PP5 in endobronchial biopsies and ASM cells. RESULTS: The production of CCL11 and CCL5 by TNF-α was insensitive to both fluticasone and dexamethasone in ASM cells from severe asthmatic compared to that in healthy subjects. Fluticasone-induced GRα nuclear translocation, phosphorylation at serine 211 and expression of GC-induced leucine zipper (GILZ) were significantly reduced in ASM cells from severe asthmatics compared to responses in healthy subjects. Levels of PP5 were increased in ASM cells from severe asthmatics and PP5 knockdown using siRNA restored fluticasone repressive action on chemokine production and its ability to induce GRα nuclear translocation and GRE-dependent GILZ expression. In vivo PP5 expression was also increased in the ASM bundles in endobronchial biopsies in severe asthmatics. CONCLUSIONS: PP5-dependent impairment of GRα function represents a novel mechanism driving GC insensitivity in ASM in severe asthma.

Funding

ERDF. Grant Number: 05567 National Institute for Health Research Leicester Respiratory Biomedical Research Unit Department of Health and National Institutes of Health. Grant Number: R01 HL111541

History

Citation

Allergy 2016

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

Allergy 2016

Publisher

Wiley

issn

0105-4538

eissn

1398-9995

Acceptance date

2016-08-06

Available date

2016-11-03

Publisher version

http://onlinelibrary.wiley.com/doi/10.1111/all.13003/abstract

Language

en

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