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Expression of the transcription factor STAT-1 alpha in insulinoma cells protects against cytotoxic effects of multiple cytokines.

Publication ,  Journal Article
Chen, G; Hohmeier, HE; Newgard, CB
Published in: J Biol Chem
January 5, 2001

Destruction of pancreatic islet beta-cells in type 1 diabetes appears to result from direct contact with infiltrating T-cells and macrophages and exposure to inflammatory cytokines such as interferon (IFN)-gamma, interleukin (IL)-1 beta, and tumor necrosis factor TNF-alpha that such cells produce. We recently reported on a method for selection of insulinoma cells that are resistant to the cytotoxic effects of inflammatory cytokines (INS-1(res)), involving their growth in progressively increasing concentrations of IL-1 beta plus IFN-gamma, and selection of surviving cells. In the current study, we have investigated the molecular mechanism of cytokine resistance in INS-1(res) cells. By focusing on the known components of the IFN-gamma receptor signaling pathway, we have discovered that expression levels of signal transducer and activator of transcription (STAT)-1 alpha are closely correlated with the cytokine-resistant and -sensitive phenotypes. That STAT-1 alpha is directly involved in development of cytokine resistance is demonstrated by an increase of viability from 10 +/- 2% in control cells to 50 +/- 6% in cells with adenovirus-mediated overexpression of STAT-1 alpha (p < 0.001) after culture of both cell groups in the presence of 100 units/ml IFN-gamma plus 10 ng/ml IL-1 beta for 48 h. The resistance to IL-1 beta plus IFN-gamma in STAT-1 alpha-expressing cells is due in part to interference with IL-1 beta-mediated stimulation of inducible nitric-oxide synthase expression and nitric oxide production. Furthermore, overexpression of STAT-1 alpha does not impair robust glucose-stimulated insulin secretion in the INS-1-derived cell line 832/13. We conclude that expression of STAT-1 alpha may be a means of protecting insulin-producing cell lines from cytokine damage, which, in conjunction with appropriate cell-impermeant macroencapsulation devices, may allow such cells to be used for insulin replacement in type 1 diabetes.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

January 5, 2001

Volume

276

Issue

1

Start / End Page

766 / 772

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Transcription Factors
  • Signal Transduction
  • Receptors, Interferon
  • Rats
  • Phosphorylation
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase
  • Nitric Oxide
 

Citation

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Chen, G., Hohmeier, H. E., & Newgard, C. B. (2001). Expression of the transcription factor STAT-1 alpha in insulinoma cells protects against cytotoxic effects of multiple cytokines. J Biol Chem, 276(1), 766–772. https://doi.org/10.1074/jbc.M008330200
Chen, G., H. E. Hohmeier, and C. B. Newgard. “Expression of the transcription factor STAT-1 alpha in insulinoma cells protects against cytotoxic effects of multiple cytokines.J Biol Chem 276, no. 1 (January 5, 2001): 766–72. https://doi.org/10.1074/jbc.M008330200.
Chen, G., et al. “Expression of the transcription factor STAT-1 alpha in insulinoma cells protects against cytotoxic effects of multiple cytokines.J Biol Chem, vol. 276, no. 1, Jan. 2001, pp. 766–72. Pubmed, doi:10.1074/jbc.M008330200.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

January 5, 2001

Volume

276

Issue

1

Start / End Page

766 / 772

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Transcription Factors
  • Signal Transduction
  • Receptors, Interferon
  • Rats
  • Phosphorylation
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase
  • Nitric Oxide