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IgE-receptor activation induces survival and Bfl-1 expression in human mast cells but not basophils
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
2006 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 61, no 9, 1040-1046 p.Article in journal (Refereed) Published
Abstract [en]

Background: The contribution of mast cells to the pathology of allergic diseases are facilitated by their long life span in tissue and ability to regranulate. Bcl-2 genes are one of the main regulators of cell death and survival. The aim of this study was to elucidate the mechanisms responsible for mast cell survival in allergy.

Methods: Bcl-2 family gene expression in human mast cells and basophils was analyzed by ribonuclease protection assay and by reverse-transcriptase polymerase chain reaction. Cell survival was measured by mixing cells with the vital dye, trypan blue, and the number of living cells was enumerated. Apoptotic cells were measured by a Cell Death Detection ELISA.

Results: We found that cross-linking of Fc epsilon RI on human cord blood cultured mast cells (CBCMCs) promoted cell survival and induced expression of the pro-survival gene Bfl-1. CBCMCs were found to express both Bfl-1 and Bfl-1S, two splicing variants of Bfl-1. Bfl-1 induction was mediated through Syk, PI3-kinase and intracellular calcium mobilization, since piceatannol, wortmannin and EDTA, respectively, significantly reduced Bfl-1 expression levels. In contrast to CBCMCs, no evidence was found for Bfl-1 expression and survival promotion in human basophils.

Conclusions: Immunoglobulin E (IgE)-dependent activation-induced mast cell survival was correlated with Bfl-1 gene upregulation, providing a possible explanation for mast cell longevity in allergic reactions.

Place, publisher, year, edition, pages
2006. Vol. 61, no 9, 1040-1046 p.
Keyword [en]
A1, basophil, Bcl-2 family members, Bfl-1, Fc epsilon RI, mast cell
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-92471DOI: 10.1111/j.1398-9995.2006.01024.xISI: 000239514400003PubMedID: 16918505OAI: oai:DiVA.org:uu-92471DiVA: diva2:165559
Available from: 2004-11-26 Created: 2004-11-26 Last updated: 2011-06-29Bibliographically approved
In thesis
1. Regulation of Mast Cell Survival
Open this publication in new window or tab >>Regulation of Mast Cell Survival
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mast cells are long-lived effector cells of importance for both acute and chronic inflammations. Mast cells can be activated in many different ways, leading to the release of inflammatory mediators. In contrast to most other inflammatory cells, activated mast cells have the capacity to recover, regranulate and thereby be activated again.

In this thesis I have investigated the mechanisms involved in regulating activation-induced mast cell survival. We have found that cross-linking of FcεRI-bound IgE with an antigen (IgER-CL) induces a survival program in mast cells. Upon IgER-CL, mouse and human mast cells upregulate the pro-survival Bcl-2 family gene A1/Bfl-1. A1-/- mast cells degranulate upon FcεRI activation but they cannot recover most likely due to the lack of A1. Sensitized and provoked A1-/- mice exhibit lower amounts of mast cells compared to littermate controls. In contrast to mast cells, no Bfl-1 expression or survival promotion can be detected in basophils after IgER-CL. Another mast cell secretagogue, an adenosine receptor agonist, neither promoted upregulation of A1 nor survival.

Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. We have found that SCF promotes survival through Akt-mediated inhibition of the forkhead transcription factor FOXO3a and its transcriptional target Bim, a BH3-only pro-apoptotic protein. SCF-treatment prevents upregulation of Bim protein expression and leads to an upregulation of Bim phosphorylation through PI3-kinase and MEK-dependent pathways. Overexpression of FOXO3a causes an upregulation of Bim and induces mast cell apoptosis, even in the presence of SCF.

Taken together, the work in this thesis demonstrates that A1/Bfl-1 and Bim play key roles in mast cell survival. These findings might be of importance in understanding the mechanisms of mast cell longevity and hence for possible new therapeutics used for mast cell-associated inflammations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 66 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1396
Pathology, mast cell, A1, Bfl-1, Bim, Bcl-2 family members, basophil, SCF, forkhead, survival, Patologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-4703 (URN)91-554-6118-2 (ISBN)
Public defence
2004-12-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved

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