Interleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy

ABSTRACT IL‐6 is a pleiotropic cytokine with complex roles in inflammation and metabolic disease. The role of IL‐6 as a pro‐ or anti‐inflammatory cytokine is still unclear. Within the pancreatic islet, IL‐6 stimulates secretion of the prosurvival incretin hormone glucagon‐like peptide 1 (GLP‐1) by α cells and acts directly on β cells to stimulate insulin secretion in vitro. Uncovering physiologic mechanisms promoting β‐cell survival under conditions of inflammation and stress can identify important pathways for diabetes prevention and treatment. Given the established role of GLP‐1 in promoting β‐cell survival, we hypothesized that IL‐6 may also directly protect β cells from apoptosis. Herein, we show that IL‐6 robustly activates signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in autophagy. IL‐6 stimulates LC3 conversion and autophagosome formation in cultured β cells. In vivo IL‐6 infusion stimulates a robust increase in lysosomes in the pancreas that is restricted to the islet. Autophagy is critical for β‐cell homeostasis, particularly under conditions of stress and increased insulin demand. The stimulation of autophagy by IL‐6 is regulated via multiple complementary mechanisms including inhibition of mammalian target of rapamycin complex 1 (mTORC1) and activation of Akt, ultimately leading to increases in autophagy enzyme production. Pretreatment with IL‐6 renders β cells resistant to apoptosis induced by proinflammatory cytokines, and inhibition of autophagy with chloroquine prevents the ability of IL‐6 to protect from apoptosis. Importantly, we find that IL‐6 can activate STAT3 and the autophagy enzyme GABARAPL1 in human islets. We also see evidence of decreased IL‐6 pathway signaling in islets from donors with type 2 diabetes. On the basis of our results, we propose direct stimulation of autophagy as a novel mechanism for IL‐6‐mediated protection of β cells from stress‐induced apoptosis.—Linnemann, A. K., Blumer, J., Marasco, M. R., Battiola, T. J., Umhoefer, H. M., Han, J. Y., Lamming, D. W., Davis, D. B. Interleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy. FASEB J. 31, 4140–4152 (2017). www.fasebj.org —Linnemann, Amelia K., Blumer, Joseph, Marasco, Michelle R., Battiola, Therese J., Umhoefer, Heidi M., Han, Jee Young, Lamming, Dudley W., Davis, Dawn Belt Interleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy. FASEB J. 31, 4140–4152 (2017)