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Pro- and antiapoptotic proteins regulate apoptosis but do not protect against cytokine-mediated cytotoxicity in rat islets and beta-cell lines.

Publication ,  Journal Article
Collier, JJ; Fueger, PT; Hohmeier, HE; Newgard, CB
Published in: Diabetes
May 2006

Type 1 diabetes results from islet beta-cell death and dysfunction induced by an autoimmune mechanism. Proinflammatory cytokines such as interleukin-1beta and gamma-interferon are mediators of this beta-cell cytotoxicity, but the mechanism by which damage occurs is not well understood. In the current study, we present multiple lines of evidence supporting the conclusion that cytokine-induced killing of rat beta-cells occurs predominantly by a nonapoptotic mechanism, including the following: 1) A rat beta-cell line selected for resistance to cytokine-induced cytotoxicity (833/15) is equally sensitive to killing by the apoptosis-inducing agents camptothecin and etoposide as a cytokine-sensitive cell line (832/13). 2) Overexpression of a constitutively active form of the antiapoptotic protein kinase Akt1 in 832/13 cells provides significant protection against cell killing induced by camptothecin and etoposide but no protection against cytokine-mediated damage. 3) Small interfering RNA-mediated suppression of the proapoptotic protein Bax enhances viability of 832/13 cells upon exposure to the known apoptosis-inducing drugs but not the inflammatory cytokines. 4) Exposure of primary rat islets or 832/13 cells to the inflammatory cytokines causes cell death as evidenced by the release of adenylate kinase activity into the cell medium, with no attendant increase in caspase 3 activation or annexin V staining. In contrast, camptothecin- and etoposide-induced killing is associated with robust increases in caspase 3 activation and annexin V staining. 5) Camptothecin increases cellular ATP levels, whereas inflammatory cytokines lower ATP levels in both beta-cell lines and primary islets. We conclude that proinflammatory cytokines cause beta-cell cytotoxicity primarily through a nonapoptotic mechanism linked to a decline in ATP levels.

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Published In

Diabetes

DOI

ISSN

0012-1797

Publication Date

May 2006

Volume

55

Issue

5

Start / End Page

1398 / 1406

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • bcl-2 Homologous Antagonist-Killer Protein
  • Transfection
  • Rats
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-akt
  • Islets of Langerhans
  • Interleukin-1
  • Interferon-gamma
  • Gene Expression Regulation
 

Citation

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Collier, J. J., Fueger, P. T., Hohmeier, H. E., & Newgard, C. B. (2006). Pro- and antiapoptotic proteins regulate apoptosis but do not protect against cytokine-mediated cytotoxicity in rat islets and beta-cell lines. Diabetes, 55(5), 1398–1406. https://doi.org/10.2337/db05-1000
Collier, J Jason, Patrick T. Fueger, Hans E. Hohmeier, and Christopher B. Newgard. “Pro- and antiapoptotic proteins regulate apoptosis but do not protect against cytokine-mediated cytotoxicity in rat islets and beta-cell lines.Diabetes 55, no. 5 (May 2006): 1398–1406. https://doi.org/10.2337/db05-1000.
Collier, J. Jason, et al. “Pro- and antiapoptotic proteins regulate apoptosis but do not protect against cytokine-mediated cytotoxicity in rat islets and beta-cell lines.Diabetes, vol. 55, no. 5, May 2006, pp. 1398–406. Pubmed, doi:10.2337/db05-1000.

Published In

Diabetes

DOI

ISSN

0012-1797

Publication Date

May 2006

Volume

55

Issue

5

Start / End Page

1398 / 1406

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • bcl-2 Homologous Antagonist-Killer Protein
  • Transfection
  • Rats
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-akt
  • Islets of Langerhans
  • Interleukin-1
  • Interferon-gamma
  • Gene Expression Regulation