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Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy.

Publication ,  Journal Article
Tran, VV; Chen, G; Newgard, CB; Hohmeier, HE
Published in: Diabetes
June 2003

We have been investigating the potential utility of engineered cell lines as surrogates for primary islet cells in treatment of type 1 diabetes. To this end, two strategies that have emerged for procuring cell lines with resistance to immune-mediated damage are 1) selection of cytokine-resistant cell lines by growth of INS-1 insulinoma cells in iteratively increasing concentrations of interleukin (IL)-1beta + gamma-interferon (IFN-gamma), and 2) stable overexpression of the anti-apoptotic gene bcl-2 in INS-1 cells. Herein, we show that bcl-2-overexpressing cells are resistant to the cytotoxic effects of reactive oxygen and nitrogen species (ROS/RNS), but are only modestly protected against high concentrations of IL-1beta + INF-gamma, whereas the converse is true in cytokine selected cells. We also found that the combination of bcl-2 expression and cytokine selection confers a broader spectrum of resistance than either procedure alone, such that the resultant cells are highly resistant to cytokines and ROS/RNS, with no impairment in glucose-stimulated insulin secretion. INS-1-derived cells with combined bcl-2 expression and cytokine selection are also more resistant to damage induced by coculture with mitogen-activated peripheral blood mononuclear cells. Surprisingly, application of the cytokine selection procedure to bcl-2-overexpressing cells does not result in impairment of nuclear factor-kappaB translocation, iNOS expression, and NO production, as clearly occurs upon application of the selection procedure to cells without bcl-2 overexpression. Further investigation of the diverse pathways involved in the development of cytokine and ROS/RNS resistance may define simplified and specific strategies for preservation of beta-cell mass.

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Published In

Diabetes

DOI

ISSN

0012-1797

Publication Date

June 2003

Volume

52

Issue

6

Start / End Page

1423 / 1432

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Tissue Engineering
  • S-Nitroso-N-Acetylpenicillamine
  • Reverse Transcriptase Polymerase Chain Reaction
  • Recombinant Proteins
  • Rats
  • Proto-Oncogene Proteins c-bcl-2
  • Pancreatic Neoplasms
  • Oxidative Stress
 

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Tran, V. V., Chen, G., Newgard, C. B., & Hohmeier, H. E. (2003). Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy. Diabetes, 52(6), 1423–1432. https://doi.org/10.2337/diabetes.52.6.1423
Tran, Veronique Vien, Guoxun Chen, Christopher B. Newgard, and Hans E. Hohmeier. “Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy.Diabetes 52, no. 6 (June 2003): 1423–32. https://doi.org/10.2337/diabetes.52.6.1423.
Tran, Veronique Vien, et al. “Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy.Diabetes, vol. 52, no. 6, June 2003, pp. 1423–32. Pubmed, doi:10.2337/diabetes.52.6.1423.

Published In

Diabetes

DOI

ISSN

0012-1797

Publication Date

June 2003

Volume

52

Issue

6

Start / End Page

1423 / 1432

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Tissue Engineering
  • S-Nitroso-N-Acetylpenicillamine
  • Reverse Transcriptase Polymerase Chain Reaction
  • Recombinant Proteins
  • Rats
  • Proto-Oncogene Proteins c-bcl-2
  • Pancreatic Neoplasms
  • Oxidative Stress