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

Raghu Mirmira, Amelia Linnemann, Christopher A. Reissaus, John E. Cupit, Evan M. Appleman, Raghavendra G. Mirmira, Amelia K. Linnemann

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1576-1588
Number of pages13
JournalDiabetes
Volume67
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Autophagy
Interleukin-6
Oxidative Stress
Antioxidants
Reactive Oxygen Species
Mitochondrial Degradation
Islets of Langerhans
Alloxan
Streptozocin
Rodentia
Cell Survival
Mitochondria
Cell Death
Animal Models
Apoptosis
Cytokines

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Mirmira, R., Linnemann, A., Reissaus, C. A., Cupit, J. E., Appleman, E. M., Mirmira, R. G., & Linnemann, A. K. (2018). Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response. Diabetes, 67(8), 1576-1588. https://doi.org/10.2337/db17-1280

Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response. / Mirmira, Raghu; Linnemann, Amelia; Reissaus, Christopher A.; Cupit, John E.; Appleman, Evan M.; Mirmira, Raghavendra G.; Linnemann, Amelia K.

In: Diabetes, Vol. 67, No. 8, 01.08.2018, p. 1576-1588.

Research output: Contribution to journalArticle

Mirmira, R, Linnemann, A, Reissaus, CA, Cupit, JE, Appleman, EM, Mirmira, RG & Linnemann, AK 2018, 'Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response', Diabetes, vol. 67, no. 8, pp. 1576-1588. https://doi.org/10.2337/db17-1280
Mirmira, Raghu ; Linnemann, Amelia ; Reissaus, Christopher A. ; Cupit, John E. ; Appleman, Evan M. ; Mirmira, Raghavendra G. ; Linnemann, Amelia K. / Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response. In: Diabetes. 2018 ; Vol. 67, No. 8. pp. 1576-1588.
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