Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response
Autor: | John E. Cupit, Raghavendra G. Mirmira, Abass M. Conteh, Amelia K. Linnemann, Michelle Marasco, Evan M. Appleman, Christopher A. Reissaus |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Programmed cell death Endocrinology Diabetes and Metabolism Mice Transgenic Tissue Banks Mitochondrion medicine.disease_cause Streptozocin Diabetes Mellitus Experimental Tissue Culture Techniques 03 medical and health sciences Random Allocation Cell Line Tumor Insulin-Secreting Cells Mitophagy Alloxan Internal Medicine medicine Autophagy Animals Humans Interleukin 6 chemistry.chemical_classification Mice Knockout Reactive oxygen species biology Interleukin-6 Streptozotocin Receptors Interleukin-6 Recombinant Proteins 3. Good health Cell biology Rats Mice Inbred C57BL Oxidative Stress 030104 developmental biology chemistry Islet Studies biology.protein Reactive Oxygen Species Oxidative stress Biomarkers medicine.drug Signal Transduction |
Zdroj: | Diabetes |
ISSN: | 1939-327X 0012-1797 |
Popis: | Production of reactive oxygen species (ROS) is a key instigator of β-cell dysfunction in diabetes. The pleiotropic cytokine interleukin 6 (IL-6) has previously been linked to β-cell autophagy but has not been studied in the context of β-cell antioxidant response. We used a combination of animal models of diabetes and analysis of cultured human islets and rodent β-cells to study how IL-6 influences antioxidant response. We show that IL-6 couples autophagy to antioxidant response and thereby reduces ROS in β-cells and human islets. β-Cell-specific loss of IL-6 signaling in vivo renders mice more susceptible to oxidative damage and cell death through the selective β-cell toxins streptozotocin and alloxan. IL-6-driven ROS reduction is associated with an increase in the master antioxidant factor NRF2, which rapidly translocates to the mitochondria to decrease mitochondrial activity and stimulate mitophagy. IL-6 also initiates a robust transient decrease in cellular cAMP levels, likely contributing to the stimulation of mitophagy to mitigate ROS. Our findings suggest that coupling autophagy to antioxidant response in β-cells leads to stress adaptation that can reduce cellular apoptosis. These findings have implications for β-cell survival under diabetogenic conditions and present novel targets for therapeutic intervention. |
Databáze: | OpenAIRE |
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