Involvement of MicroRNAs in the Cytotoxic Effects Exerted by Proinflammatory Cytokines on Pancreatic β-Cells

  1. Romano Regazzi1
  1. 1Department of Cell Biology and Morphology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland;
  2. 2Department of Cell Physiology and Metabolism, School of Medicine, University of Geneva, Geneva, Switzerland;
  3. 3Department of Genetic Medicine and Development, Geneva Eurexpress, School of Medicine, University of Geneva, Geneva, Switzerland;
  4. 4Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  1. Corresponding author: Romano Regazzi, romano.regazzi{at}unil.ch.

Abstract

OBJECTIVE Pancreatic β-cells exposed to proinflammatory cytokines display alterations in gene expression resulting in defective insulin secretion and apoptosis. MicroRNAs are small noncoding RNAs emerging as key regulators of gene expression. Here, we evaluated the contribution of microRNAs to cytokine-mediated β-cell cytotoxicity.

RESEARCH DESIGN AND METHODS We used global microarray profiling and real-time PCR analysis to detect changes in microRNA expression in β-cells exposed to cytokines and in islets of pre-diabetic NOD mice. We assessed the involvement of the microRNAs affected in cytokine-mediated β-cell failure by modifying their expression in insulin-secreting MIN6 cells.

RESULTS We found that IL-1β and TNF-α induce the expression of miR-21, miR-34a, and miR-146a both in MIN6 cells and human pancreatic islets. We further show an increase of these microRNAs in islets of NOD mice during development of pre-diabetic insulitis. Blocking miR-21, miR-34a, or miR-146a function using antisense molecules did not restore insulin-promoter activity but prevented the reduction in glucose-induced insulin secretion observed upon IL-1β exposure. Moreover, anti–miR-34a and anti–miR-146a treatment protected MIN6 cells from cytokine-triggered cell death.

CONCLUSIONS Our data identify miR-21, miR-34a, and miR-146a as novel players in β-cell failure elicited in vitro and in vivo by proinflammatory cytokines, notably during the development of peri-insulitis that precedes overt diabetes in NOD mice.

Footnotes

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    • Received June 16, 2009.
    • Accepted January 6, 2010.

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  1. Diabetes vol. 59 no. 4 978-986
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