Proinflammatory cytokines activate the intrinsic apoptotic pathway in beta-cells
Research output: Contribution to journal › Journal article › Research › peer-review
OBJECTIVE: Proinflammatory cytokines are cytotoxic to beta-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 beta-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 beta-cells. RESEARCH DESIGN AND METHODS: Human and rat islets and INS-1 cells were exposed to a combination of proinflammatory cytokines (interleukin-1beta, interferon-gamma, and/or tumor necrosis factor-alpha). 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 beta-cell death and suggest a functional role of calcineurin-mediated Bad Ser136 dephosphorylation and Bax activity in cytokine-induced apoptosis.
Original language | English |
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Journal | Diabetes |
Volume | 58 |
Issue number | 8 |
Pages (from-to) | 1807-15 |
Number of pages | 8 |
ISSN | 0012-1797 |
DOIs | |
Publication status | Published - 2009 |
Bibliographical note
Keywords: Animals; Apoptosis; Cadaver; Caspase 9; Cell Death; Cytokines; Humans; Insulin-Secreting Cells; Interferon-gamma; Interleukin-1beta; Rats; Rats, Wistar; Tissue Donors; Tumor Necrosis Factor-alpha
ID: 18698233