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.
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.
Giannoukakis
N
N
Department of Molecular Genetics and Biochemistry, Children's Hospital, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Rudert
W A
WA
Ghivizzani
S C
SC
Gambotto
A
A
Ricordi
C
C
Trucco
M
M
Robbins
P D
PD
D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D005947:Glucose; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007515:Islets of Langerhans / Q000473:pathology*; D016381:Islets of Langerhans Transplantation; D009569:Nitric Oxide / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000235:genetics; D012795:Sialoglycoproteins / Q000235:genetics*; D014184:Transplantation, Homologous; D014779:Virus Replication
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D009569:Nitric Oxide; D005947:Glucose