Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response

Diabetes. 2018 Aug;67(8):1576-1588. doi: 10.2337/db17-1280. Epub 2018 May 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alloxan / toxicity
  • Animals
  • Autophagy* / drug effects
  • Biomarkers / metabolism
  • Cell Line, Tumor
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / immunology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Oxidative Stress* / drug effects
  • Random Allocation
  • Rats
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Receptors, Interleukin-6 / agonists*
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / metabolism
  • Recombinant Proteins / metabolism
  • Signal Transduction* / drug effects
  • Streptozocin / toxicity
  • Tissue Banks
  • Tissue Culture Techniques


  • Biomarkers
  • IL6 protein, human
  • IL6R protein, human
  • Interleukin-6
  • Reactive Oxygen Species
  • Receptors, Interleukin-6
  • Recombinant Proteins
  • interleukin-6, mouse
  • Streptozocin
  • Alloxan