Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Regulation of Mast Cell Survival
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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. , p. 66
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1396
Keywords [en]
Pathology, mast cell, A1, Bfl-1, Bim, Bcl-2 family members, basophil, SCF, forkhead, survival
Keywords [sv]
Patologi
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-4703ISBN: 91-554-6118-2 (print)OAI: oai:DiVA.org:uu-4703DiVA, id: diva2:165561
Public defence
2004-12-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-11-26 Created: 2004-11-26 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Essential Role of the bcl-2 Homologue A1 in Mast Cell Survival After Allergic Activation
Open this publication in new window or tab >>Essential Role of the bcl-2 Homologue A1 in Mast Cell Survival After Allergic Activation
Show others...
2001 In: Journal of Experimental Medicine, ISSN 0022-1007, Vol. 194, no 11, p. 1561-1569Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92469 (URN)
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved
2. Activation of mast cells by immunoglobulin E-receptor cross-linkage, but not through adenosine receptors, induces A1 expression and promotes survival
Open this publication in new window or tab >>Activation of mast cells by immunoglobulin E-receptor cross-linkage, but not through adenosine receptors, induces A1 expression and promotes survival
2003 In: Clinical and Experimental Allergy, ISSN 0954-7894, Vol. 33, no 8, p. 1135-1140Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92470 (URN)
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved
3. IgE-receptor activation induces survival and Bfl-1 expression in human mast cells but not basophils
Open this publication in new window or tab >>IgE-receptor activation induces survival and Bfl-1 expression in human mast cells but not basophils
2006 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 61, no 9, p. 1040-1046Article 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.

Keywords
A1, basophil, Bcl-2 family members, Bfl-1, Fc epsilon RI, mast cell
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92471 (URN)10.1111/j.1398-9995.2006.01024.x (DOI)000239514400003 ()16918505 (PubMedID)
Available from: 2004-11-26 Created: 2004-11-26 Last updated: 2017-12-14Bibliographically approved
4. Stem cell factor promotes mast cell survival via inactivation of FOXO3a mediated transcriptional induction and MEK regulated phosphorylation of the pro-apoptotic protein Bim
Open this publication in new window or tab >>Stem cell factor promotes mast cell survival via inactivation of FOXO3a mediated transcriptional induction and MEK regulated phosphorylation of the pro-apoptotic protein Bim
Show others...
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-92472 (URN)
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved

Open Access in DiVA

fulltext(627 kB)1183 downloads
File information
File name FULLTEXT01.pdfFile size 627 kBChecksum MD5
28ebc79af63a3454a74954153cfa64dd41f0cfe6998e548d2cf41d77d2db9caf90fce413
Type fulltextMimetype application/pdf
Buy this publication >>

By organisation
Department of Genetics and Pathology
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 1183 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 982 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf