Proinflammatory Cytokines Activate the Intrinsic Apoptotic Pathway in β-Cells

  1. Lars G. Grunnet1,2,
  2. Reid Aikin3,4,
  3. Morten F. Tonnesen1,
  4. Steven Paraskevas4,
  5. Lykke Blaabjerg1,
  6. Joachim Størling1,
  7. Lawrence Rosenberg4,
  8. Nils Billestrup1,
  9. Dusica Maysinger3 and
  10. Thomas Mandrup-Poulsen1,2
  1. 1Department of Translational Diabetology, Steno Diabetes Center, Gentofte, Denmark;
  2. 2Core Unit for Medical Research Methodology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark;
  3. 3Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada;
  4. 4Department of Surgery, McGill University, Montreal, Quebec, Canada.
  1. Corresponding author: Thomas Mandrup-Poulsen, tmpo{at}, or Lars G. Grunnet, lggrunnet{at}
  1. L.G.G. and R.A. contributed equally to this article.


OBJECTIVE Proinflammatory cytokines are cytotoxic to β-cells and have been implicated in the pathogenesis of type 1 diabetes and islet graft failure. The importance of the intrinsic mitochondrial apoptotic pathway in cytokine-induced β-cell death is unclear. Here, cytokine activation of the intrinsic apoptotic pathway and the role of the two proapoptotic Bcl-2 proteins, Bad and Bax, were examined in β-cells.

RESEARCH DESIGN AND METHODS Human and rat islets and INS-1 cells were exposed to a combination of proinflammatory cytokines (interleukin-1β, interferon-γ, and/or tumor necrosis factor-α). Activation of Bad was determined by Ser136 dephosphorylation, mitochondrial stress by changes in mitochondrial metabolic activity and cytochrome c release, downstream apoptotic signaling by activation of caspase-9 and -3, and DNA fragmentation. The inhibitors FK506 and V5 were used to investigate the role of Bad and Bax activation, respectively.

RESULTS We found that proinflammatory cytokines induced calcineurin-dependent dephosphorylation of Bad Ser136, mitochondrial stress, cytochrome c release, activation of caspase-9 and -3, and DNA fragmentation. Inhibition of Bad Ser136 dephosphorylation or Bax was found to inhibit cytokine-induced intrinsic proapoptotic signaling.

CONCLUSIONS Our findings demonstrate that the intrinsic mitochondrial apoptotic pathway contributes significantly to cytokine-induced β-cell death and suggest a functional role of calcineurin-mediated Bad Ser136 dephosphorylation and Bax activity in cytokine-induced apoptosis.


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  • See accompanying commentary, p. 1725.

    • Received February 8, 2008.
    • Accepted May 4, 2009.
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