期刊
FASEB JOURNAL
卷 31, 期 9, 页码 4140-4152出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201700061RR
关键词
pancreas; islet; diabetes
资金
- U.S. National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K01DK102492]
- Herman B. Wells Center for Pediatric Research at Indiana University School of Medicine
- Pilot and Feasibility Award within the Indiana University CDMD NIH/NIDDK Grant [P30 DK097512]
- NIH National Institute on Aging [AG041765, AG050135]
- Glenn Foundation Award for Research in the Biological Mechanisms of Aging
- UW-Madison Department of Medicine
- American Federation for Aging Research (AFAR)
- Department of Veterans Affairs [I01BX001880]
- NIH/NIDDK [R01DK110324]
- University of Wisconsin-Madison Department of Medicine
IL-6 is a pleiotropic cytokinewith 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 a cells and acts directly on beta cells to stimulate insulin secretion in vitro. Uncovering physiologic mechanisms promoting beta-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 beta-cell survival, we hypothesized that IL-6 may also directly protect beta 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 beta 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 beta-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 beta 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 beta cells from stress-induced apoptosis.
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