Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic β-cells

E Roggli, A Britan, S Gattesco, N Lin-Marq… - Diabetes, 2010 - Am Diabetes Assoc
E Roggli, A Britan, S Gattesco, N Lin-Marq, A Abderrahmani, P Meda, R Regazzi
Diabetes, 2010Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc