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Diabetes, Vol 48, Issue 9 1730-1736, Copyright © 1999 by American Diabetes Association

ARTICLES

Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-1beta-induced beta-cell impairment and activation of islet cell apoptosis in vitro

N Giannoukakis, WA Rudert, SC Ghivizzani, A Gambotto, C Ricordi, M Trucco and PD Robbins
Department of Molecular Genetics and Biochemistry, Children's Hospital, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.

The beta-cells in the pancreatic islets of Langerhans are the targets of autoreactive T-cells and are destroyed in type 1 diabetes. Macrophage-derived interleukin-1beta (IL-1beta) is important in eliciting beta-cell dysfunction and initiating beta-cell damage in response to microenvironmental changes within islets. In particular, IL-1beta can impair glucose-stimulated insulin production in beta-cells in vitro and can sensitize them to Fas (CD95)/FasL-triggered apoptosis. In this report, we have examined the ability to block the detrimental effects of IL-1beta by genetically modifying islets by adenoviral gene transfer to express the IL-1 receptor antagonist protein. We demonstrate that adenoviral gene delivery of the cDNA encoding the interleukin-1 receptor antagonist protein (IL-1Ra) to cultured islets results in protection of human islets in vitro against IL-1beta-induced nitric oxide formation, impairment in glucose-stimulated insulin production, and Fas-triggered apoptosis activation. Our results further support the hypothesis that IL-1beta antagonism in in situ may prevent intra-islet proinsulitic inflammatory events and may allow for an in vivo gene therapy strategy to prevent insulitis and the consequent pathogenesis of diabetes.
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