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Role of Calcium in Pancreatic Islet Cell Death by IFN-γ/TNF-α1

 Inik Chang  ;  Namjoo Cho  ;  Myung-Shik Lee  ;  Sung Joon Kim  ;  Joo Hyun Nam  ;  Ji-Eun Woo  ;  Eunshil Kim  ;  Ja Young Kim  ;  Sunshin Kim 
 JOURNAL OF IMMUNOLOGY, Vol.172(11) : 7008-7014, 2004 
Journal Title
Issue Date
Animals ; Apoptosis* ; Calcineurin/physiology ; Calcium/physiology* ; Carrier Proteins/metabolism ; Caspases/metabolism ; Cytochromes c/metabolism ; Interferon-gamma/pharmacology* ; Islets of Langerhans/pathology* ; Mice ; Mice, Inbred NOD ; Phosphorylation ; Protein Transport ; Tumor Necrosis Factor-alpha/pharmacology* ; bcl-Associated Death Protein
We studied the intracellular events associated with pancreatic β cell apoptosis by IFN-γ/TNF-α synergism. IFN-γ/TNF-α treatment of MIN6N8 insulinoma cells increased the amplitude of high voltage-activated Ca2+ currents, while treatment with IFN-γ or TNF-α alone did not. Cytosolic Ca2+ concentration ([Ca2+]c) was also increased by IFN-γ/TNF-α treatment. Blockade of L-type Ca2+ channel by nifedipine abrogated death of insulinoma cells by IFN-γ/TNF-α. Diazoxide that attenuates voltage-activated Ca2+ currents inhibited MIN6N8 cell death by IFN-γ/TNF-α, 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-γ/TNF-α. Following the increase in [Ca2+]c, calpain was activated, and calpain inhibitors decreased insulinoma cell death by IFN-γ/TNF-α. As a downstream of calpain, calcineurin was activated and the inhibition of calcineurin activation by FK506 diminished insulinoma cell death by IFN-γ/TNF-α. BAD phosphorylation was decreased by IFN-γ/TNF-α because of the increased calcineurin activity, which was reversed by FK506. IFN-γ/TNF-α 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-γ/TNF-α treatment. These results indicate that IFN-γ/TNF-α synergism induces pancreatic β 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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2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Chang, In Ik(장인익)
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