| First Author | Linnemann AK | Year | 2017 |
| Journal | FASEB J | Volume | 31 |
| Issue | 9 | Pages | 4140-4152 |
| PubMed ID | 28592636 | Mgi Jnum | J:247774 |
| Mgi Id | MGI:5925461 | Doi | 10.1096/fj.201700061RR |
| Citation | Linnemann AK, et al. (2017) Interleukin 6 protects pancreatic beta cells from apoptosis by stimulation of autophagy. FASEB J 31(9):4140-4152 |
| abstractText | 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 alpha 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.-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 beta cells from apoptosis by stimulation of autophagy. |
