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Permanent link (DOI): https://doi.org/10.7939/R3W969

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Expression and functional significance of the cystic fibrosis transmembrane conductance regulator (CFTR) in human mast cells Open Access

Descriptions

Other title
Subject/Keyword
cftr
mast cells
cystic fibrosis
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Déry, René
Supervisor and department
Dr. A. Dean Befus (Medicine)
Examining committee member and department
Dr. Soman Abraham (Pathology, Duke University)
Dr. Neil Brown (Medicine)
Dr. James Young (Physiology)
Dr. Marek Duszyk (Physiology)
Dr. Bernard Thébaud (Pediatrics)
Dr. Dean Befus (Medicine)
Department
Medicine
Specialization

Date accepted
2009-10-08T14:34:42Z
Graduation date
2009-11
Degree
PhD
Degree level
Doctoral
Abstract
Mast cells (MC) are present in nearly all tissues in the body and participate in many physiological processes including allergy, tissue remodelling, fibrosis, angiogenesis, and autoimmunity. They can be activated by many stimuli, including allergic and innate immune stimulation. When activated, MC release mediators through which they can regulate inflammatory processes. Recently, we have discovered that rat and human MC express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the gene responsible for Cystic Fibrosis (CF). We showed that CFTR had functional activity in MC and its expression was differentially regulated by IFNg. In this thesis, we compared CFTR expression between MC and epithelial cells (EC) by Western blot analysis and found that CFTR expression in MC is similar to that in EC, but there are some differences which suggest either glycosylation or post-transcriptional/translational differences between MC and EC. We also explored the role of CFTR in human MC secretion from various cellular compartments, in response to various stimuli. When we blocked CFTR using pharmacological inhibitors, there was an inhibition of cAMP-dependent Cl- flux. Our data also shows that CFTR pharmacological inhibition had no effect on IgE/anti-IgE-mediated b-hexosaminidase or eicosanoid release from MC. When we stimulated MC with either IgE/anti-IgE or the adenosine receptor agonist NECA (3 uM) for 24h in the presence of CFTR inhibitors, secretion of several mediators appeared to be dysregulated including IL-8, MIF, IL-13, IL-16, PAI-1 and CCL1. To add to these findings, we also used short hairpin RNA (shRNA) to reduce CFTR expression in MC. CFTR deficient MC were unresponsive to NECA and showed reduced constitutive IL-6 secretion. Finally, we cultured MC from CF and non-CF donor peripheral blood progenitors and compared several phenotypic and functional aspects of the cells. We saw no difference in growth, protease content and surface marker expression between CF and non-CF MC, but stimulation of the cells with IgE/anti-IgE or Pseudomonas aeruginosa appeared to differentially induce cytokine synthesis and secretion from CF and non-CF MC. These findings suggest that MC function is dysregulated in CF and that CF MC may be involved in the pathophysiology of CF.
Language
English
DOI
doi:10.7939/R3W969
Rights
License granted by Rene Dery (rene.dery@ualberta.ca) on 2009-10-08T03:59:05Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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