Proinflammatory cytokines activate the intrinsic apoptotic pathway in beta-cells

Lars G Grunnet, Reid Aikin, Morten F Tonnesen, Steven Paraskevas, Lykke Blaabjerg, Joachim Størling, Lawrence Rosenberg, Nils Billestrup, Dusica Maysinger, Thomas Mandrup-Poulsen

    181 Citationer (Scopus)

    Abstract

    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.

    OriginalsprogEngelsk
    TidsskriftDiabetes
    Vol/bind58
    Udgave nummer8
    Sider (fra-til)1807-15
    Antal sider9
    ISSN0012-1797
    DOI
    StatusUdgivet - aug. 2009

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