Proinflammatory cytokines activate the intrinsic apoptotic pathway in β-cells
LG Grunnet, R Aikin, MF Tonnesen, S Paraskevas… - Diabetes, 2009 - Am Diabetes Assoc
LG Grunnet, R Aikin, MF Tonnesen, S Paraskevas, L Blaabjerg, J Størling, L Rosenberg…
Diabetes, 2009•Am Diabetes AssocOBJECTIVE 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 …
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 …
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.
Am Diabetes Assoc