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 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. 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 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.

Islet macrophages drive islet vascular remodeling and compensatory hyperinsulinemia in the early stages of diabetes

“…We successfully depleted macrophages from human islets using clodronate ex vivo and observed that VEGF-A along with TNFα are significantly reduced. Unlike mouse islets, IL-6 was increased in macrophage depleted human islets and this observation is particularly intriguing because a number of studies allude to the β-cells protective effects of IL-6 (42)(43)(44). Nonetheless, similar to mouse islets, there was no significant change in the β-cell gene expression profile in human islets when macrophages were depleted further supporting the notion that islet macrophages have a greater impact on islet vasculature more so compared to a direct impact on β-cells.…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…93 In fact, basal autophagy has been proposed to play a pivotal role in sustaining mitochondrial function in lymphoma, and low CQ concentration may cause apoptosis in susceptible lymphoma cells. 100 Failure of progenitor cells to regulate autophagy during tissue regeneration can contribute to carcinogenesis. 95 Lysosomal proteolysis enables mitochondrial quality control in rat hippocampus, a process impaired by CQ.…”

“…165 Figure 2. 100 One can then ask, how do cells reprogram expression from inflammatory genes to autophagy genes if both share some of their transcriptional activators? In triple-negative breast cancer, the overexpression of proteasome and autophagic components (their gene products are also involved in IjBa degradation) is a positive prognostic factor, while in non-triple-negative breast cancer, it is IjBa that becomes a positive prognostic factor.…”

“…99 In the pancreas of individuals with type 2 diabetes, cytokine interleukin-6 (IL-6) induces autophagy and protects pancreatic beta cells from apoptosis whereas CQ causes apoptosis and thereby elicits tissue damage. 100 Failure of progenitor cells to regulate autophagy during tissue regeneration can contribute to carcinogenesis. 37,68 Likewise, cells can activate autophagic degradation of proteins as a compensatory mechanism under drug-induced cytotoxic stress.…”

“…NF-jB-target gene IL-6 limits autophagy in healthy tissues. 100 One can then ask, how do cells reprogram expression from inflammatory genes to autophagy genes if both share some of their transcriptional activators? The answer probably lies in the recruitment of chromatin regulators, whose activities are regulated through metabolic functions.…”