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/TNF-
1
* Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and
Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Korea
We studied the intracellular events associated with pancreatic 
cell apoptosis by IFN-
/TNF-
synergism. IFN-/TNF- treatment of MIN6N8 insulinoma cells increased the amplitude of high voltage-activated Ca2+ currents, while treatment with IFN- or TNF- alone did not. Cytosolic Ca2+ concentration ([Ca2+]c) was also increased by IFN-/TNF- treatment. Blockade of L-type Ca2+ channel by nifedipine abrogated death of insulinoma cells by IFN-/TNF-. Diazoxide that attenuates voltage-activated Ca2+ currents inhibited MIN6N8 cell death by IFN-/TNF-, while glibenclamide that accentuates voltage-activated Ca2+ currents augmented insulinoma cell death. A protein kinase C inhibitor attenuated MIN6N8 cell death and the increase in [Ca2+]c by IFN-/TNF-. Following the increase in [Ca2+]c, calpain was activated, and calpain inhibitors decreased insulinoma cell death by IFN-/TNF-. As a downstream of calpain, calcineurin was activated and the inhibition of calcineurin activation by FK506 diminished insulinoma cell death by IFN-/TNF-. BAD phosphorylation was decreased by IFN-/TNF- because of the increased calcineurin activity, which was reversed by FK506. IFN-/TNF- induced cytochrome c translocation from mitochondria to cytoplasm and activation of caspase-9. Effector caspases such as caspase-3 or -7 were also activated by IFN-/TNF- treatment. These results indicate that IFN-/TNF- synergism induces pancreatic cell apoptosis by Ca2+ channel activation followed by downstream intracellular events such as mitochondrial events and caspase activation and also suggest the therapeutic potential of Ca2+ modulation in type 1 diabetes.
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