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Short term exposure of beta cells to low concentrations of interleukin-1? improves insulin secretion through focal adhesion and actin remodeling and regulation of gene expression.

ABSTRACT: Type 2 diabetes involves defective insulin secretion with islet inflammation governed in part by IL-1?. Prolonged exposure of islets to high concentrations of IL-1? (>24 h, 20 ng/ml) impairs beta cell function and survival. Conversely, exposure to lower concentrations of IL-1? for >24 h improves these same parameters. The impact on insulin secretion of shorter exposure times to IL-1? and the underlying molecular mechanisms are poorly understood and were the focus of this study. Treatment of rat primary beta cells, as well as rat or human whole islets, with 0.1 ng/ml IL-1? for 2 h increased glucose-stimulated (but not basal) insulin secretion, whereas 20 ng/ml was without effect. Similar differential effects of IL-1? depending on concentration were observed after 15 min of KCl stimulation but were prevented by diazoxide. Studies on sorted rat beta cells indicated that the enhancement of stimulated secretion by 0.1 ng/ml IL-1? was mediated by the NF-?B pathway and c-JUN/JNK pathway acting in parallel to elicit focal adhesion remodeling and the phosphorylation of paxillin independently of upstream regulation by focal adhesion kinase. Because the beneficial effect of IL-1? was dependent in part upon transcription, gene expression was analyzed by RNAseq. There were 18 genes regulated uniquely by 0.1 but not 20 ng/ml IL-1?, which are mostly involved in transcription and apoptosis. These results indicate that 2 h of exposure of beta cells to a low but not a high concentration of IL-1? enhances glucose-stimulated insulin secretion through focal adhesion and actin remodeling, as well as modulation of gene expression.

SUBMITTER: Arous C

PROVIDER: S-EPMC4358297 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Short term exposure of beta cells to low concentrations of interleukin-1β improves insulin secretion through focal adhesion and actin remodeling and regulation of gene expression.

Arous Caroline C Ferreira Pedro G PG Dermitzakis Emmanouil T ET Halban Philippe A PA

The Journal of biological chemistry 20150113 10

Type 2 diabetes involves defective insulin secretion with islet inflammation governed in part by IL-1β. Prolonged exposure of islets to high concentrations of IL-1β (>24 h, 20 ng/ml) impairs beta cell function and survival. Conversely, exposure to lower concentrations of IL-1β for >24 h improves these same parameters. The impact on insulin secretion of shorter exposure times to IL-1β and the underlying molecular mechanisms are poorly understood and were the focus of this study. Treatment of rat ...[more]

PMID: 25586177

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Project description:Interleukin-1β (IL-1β), a major pro-inflammatory cytokine, is a leaderless cytosolic protein whose secretion does not follow the classical endoplasmic reticulum-to-Golgi pathway, and for which a canonical mechanism of secretion remains to be established. Neutrophils are essential players against bacterial and fungi infections. These cells are rapidly and massively recruited from the circulation into infected tissues and, beyond of displaying an impressive arsenal of toxic weapons effective to kill pathogens, are also an important source of IL-1β in infectious conditions. Here, we analyzed if an unconventional secretory autophagy mechanism is involved in the exportation of IL-1β by these cells. Our findings indicated that inhibition of autophagy with 3-methyladenine and Wortmannin markedly reduced IL-1β secretion induced by LPS + ATP, as did the disruption of the autophagic flux with Bafilomycin A1 and E64d. These compounds did not noticeable affect neutrophil viability ruling out that the effects on IL-1β secretion were due to cell death. Furthermore, VPS34IN-1, a specific autophagy inhibitor, was still able to reduce IL-1β secretion when added after it was synthesized. Moreover, siRNA-mediated knockdown of ATG5 markedly reduced IL-1β secretion in neutrophil-differentiated PLB985 cells. Upon LPS + ATP stimulation, IL-1β was incorporated to an autophagic compartment, as was revealed by its colocalization with LC3B by confocal microscopy. Overlapping of IL-1β-LC3B in a vesicular compartment peaked before IL-1β increased in culture supernatants. On the other hand, stimulation of autophagy by cell starvation augmented the colocalization of IL-1β and LC3B and then promoted neutrophil IL-1β secretion. In addition, specific ELISAs indicated that although both IL-1β and pro-IL-1β are released to culture supernatants upon neutrophil stimulation, autophagy only promotes IL-1β secretion. Furthermore, the serine proteases inhibitor AEBSF reduced IL-1β secretion. Moreover, IL-1β could be also found colocalizing with elastase, suggesting both some vesicles containing IL-1β intersect azurophil granules content and that serine proteases also regulate IL-1β secretion. Altogether, our findings indicate that an unconventional autophagy-mediated secretory pathway mediates IL-1β secretion in human neutrophils.

Dataset Information

Short term exposure of beta cells to low concentrations of interleukin-1? improves insulin secretion through focal adhesion and actin remodeling and regulation of gene expression.

Publications

Short term exposure of beta cells to low concentrations of interleukin-1β improves insulin secretion through focal adhesion and actin remodeling and regulation of gene expression.

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