Abstract
Elevated interleukin-1β (IL-1β) induces apoptosis in pancreatic β-cells through endoplasmic reticulum (ER) stress induction and subsequent c-jun-N-terminal kinase 1/2 (JNK1/2) activation. In earlier work we showed that JNK1/2 activation is initiated before ER stress and apoptotic induction in response to IL-1β. However, the detailed regulatory mechanisms are not completely understood. Because the ER is the organelle responsible for Ca(2+) handling and storage, here we examine the effects of IL-1β on cellular Ca(2+) movement and mitochondrial dysfunction and evaluate the role of JNK1/2. Our results show that in RINm5F cells and human primary β-cells, IL-1β alters mitochondrial membrane potential, mitochondrial permeability transition pore opening, ATP content, and reactive oxygen species production and these alterations are preceded by ER Ca(2+) release via IP3R channels and mitochondrial Ca(2+) uptake. All these events are prevented by JNK1/2 small interfering RNA (siRNA), indicating the mediating role of JNK1/2 in IL-1β-induced cellular alteration. This is accompanied by IL-1β-induced apoptosis, which is prevented by JNK1/2 siRNA and the IP3R inhibitor xestospongin C. This suggests a regulatory role of JNK1/2 in modulating the ER-mitochondrial-Ca(2+) axis by IL-1β in apoptotic cell death.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Apoptosis / drug effects*
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Blotting, Western
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Calcium / metabolism*
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Cell Line, Tumor
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Cells, Cultured
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Endoplasmic Reticulum / metabolism
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Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors
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Inositol 1,4,5-Trisphosphate Receptors / genetics
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Inositol 1,4,5-Trisphosphate Receptors / metabolism
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Insulin-Secreting Cells / cytology
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Insulin-Secreting Cells / drug effects*
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Insulin-Secreting Cells / metabolism
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Interleukin-1beta / metabolism
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Interleukin-1beta / pharmacology*
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Macrocyclic Compounds / pharmacology
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Membrane Potential, Mitochondrial / drug effects
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Microscopy, Fluorescence
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Mitochondria / metabolism
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Mitochondrial Membranes / drug effects
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Mitochondrial Membranes / physiology
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Mitogen-Activated Protein Kinase 8 / genetics
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Mitogen-Activated Protein Kinase 8 / metabolism*
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Mitogen-Activated Protein Kinase 9 / genetics
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Mitogen-Activated Protein Kinase 9 / metabolism*
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Models, Biological
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Oxazoles / pharmacology
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Permeability / drug effects
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RNA Interference
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Rats
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Reactive Oxygen Species / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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Inositol 1,4,5-Trisphosphate Receptors
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Interleukin-1beta
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Macrocyclic Compounds
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Oxazoles
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Reactive Oxygen Species
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xestospongin C
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Adenosine Triphosphate
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Mitogen-Activated Protein Kinase 9
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Mitogen-Activated Protein Kinase 8
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Calcium