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Cytokine-induced apoptosis and necrosis are preceded by disruption of the mitochondrial membrane potential in pancreatic RINm5F cells: prevention by Bcl-2
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
2002 In: Molecular and Cellular Endocrinology, Vol. 190, 75-82 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 190, 75-82 p.
Identifiers
URN: urn:nbn:se:uu:diva-91301OAI: oai:DiVA.org:uu-91301DiVA: diva2:163987
Available from: 2004-02-03 Created: 2004-02-03Bibliographically approved
In thesis
1. In vitro Studies of β-cell Death and Survival. Modulation by Adenoviral Vectors and Bcl-2 Overexpression
Open this publication in new window or tab >>In vitro Studies of β-cell Death and Survival. Modulation by Adenoviral Vectors and Bcl-2 Overexpression
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes is a multifactorial disease resulting from the selective destruction of insulin-producing β-cells within the pancreatic islets of Langerhans. The mechanisms of β-cell death are not fully understood but cytokines are important mediators of this process. In the present study we found that the combination of IL-1β, TNF-α and IFN-γ induced a nitric oxide-dependent disruption of the mitochondrial membrane potential in rat insulin-producing RINm5F-cells, which seems to be a necessary event for both RINm5F-cell apoptosis and necrosis. The antiapoptotic protein Bcl-2 was able to prevent cellular death in RINm5F cells, most probably by counteracting the mitochondrial permeability transition. These results pointed out the potential of such antiapoptotic genes as gene therapy tools, to allow enhanced resistance against autoimmune destruction of β-cells in type 1 diabetes. For this purpose we used a progesterone-antagonist (RU 486)-inducible gene transfer system to achieve an efficient and controlled Bcl-2 overexpression in primary rat β-cells. However, in our experience, prolonged in vitro culture revealed adenoviral-induced islet cell necrosis, a process that was not prevented by Bcl-2 overexpression. Moreover, we observed that specific adenoviral genotypes correlate with differential induction of necrosis in both human and rat pancreatic islet cells. Although human islet cells showed an increased resistance in terms of viral concentrations required for the induction of cell-toxicity, our results showed that they were unable to build up an efficient antiviral response following infection and that their survival was dependent on the exogenous addition of α-interferon.

In conclusion, adenoviral techniques for overexpression of antiapoptotic proteins in insulin-producing cells may provide useful tools against β-cell directed autoimmune destruction. However, understanding the specific interactions of the viral gene products with cellular proteins and how they are involved in β-cell death regulation is fundamental for an efficient and safe application of gene therapy approaches to type 1 diabetes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 40 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1320
Keyword
Cell biology, β-cell, cytokine, mitochondrial membrane potential, Bcl-2, Adenoviral vector, Adenovirus, IFN-α, Diabetes, Cellbiologi
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-3973 (URN)91-554-5859-9 (ISBN)
Public defence
2004-02-28, B21, Biomedical Centre, BMC Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-02-03 Created: 2004-02-03Bibliographically approved

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