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

Abstract

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.

Resvega Alleviates Hydroquinone-Induced Oxidative Stress in ARPE-19 Cells

“…The acute phase pro-inflammatory cytokine IL-6 has pleiotropic effects with the ability to promote inflammation and angiogenesis upon pathologic conditions, but it has also shown to be protective in the neural retina [36][37][38]. It has been shown that IL-6 linked autophagy to antioxidative response, and reduced oxidative stress via p62/SQSTM1 and nuclear factor erythroid 2-related factor 2 (NRF2) [39][40][41]. In our previous study, Resvega induced autophagic flux upon declined proteasomal degradation [22].…”

Human Heme Oxygenase-1 Induced by Interleukin-6 via JAK/STAT3 Pathways Is a Tumor Suppressor Gene in Hepatoma Cells

“…These results supported recent studies, suggesting that the upregulation of HO-1 alleviated H 2 O 2 -induced ROS and oxidative injury in HepG2 cells [49,50], although, in this study, we did not determine whether ectopic HO-1 overexpression inhibited the apoptosis of hepatoma cells. Since a recent study indicated that IL-6 drives ROS reduction by increasing Nrf 2, a transcription activator of the HO-1 gene, expression in human islet β-cells [51], further investigations into the role of IL-6-HO-1 crosstalk in hepatoma cells, in terms of ROS synthesis, are warranted.…”

Human mesenchymal stem cells–derived conditioned medium inhibits hypoxia‐induced death of neonatal porcine islets by inducing autophagy

“…On one hand, IL‐6 plays an important role in regulating metabolism, particularly glucose homoeostasis . IL‐6 has been identified as a cytoprotective molecule in inflammatory disorders, as shown in multiple pre‐clinical trials of organ transplantation, and therefore may have potential applications in clinical islet transplantation as a novel therapeutic molecule. On the other hand, IL‐6 is regarded as an inflammatory factor and an important indicator in the field of xenotransplantation .…”