Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an Ikappa B repressor.
Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that inhibits beta cell function and promotes Fas-triggered apoptosis. IL-1beta is thought to act early in the initiation of the autoimmune destruction of pancreatic beta cells in type I diabetes. IL-1beta promotes beta cell impairment, in part, by activating NF-kappaB transcription factor-dependent signaling pathways. We have examined whether beta cells could be protected from the effects of IL-1beta by overexpressing an inhibitor of NF-kappaB activity, IkappaB, by adenoviral gene transfer to intact human islets in culture. Infection of islets with an adenoviral vector encoding a non-phosphorylatable, non-degradable variant of IkappaBalpha resulted in normal insulin responses to glucose in the presence of IL-1beta. Furthermore, nitric oxide production was prevented and, more importantly, Fas-triggered apoptosis was inhibited following IkappaBalpha gene transfer. These results suggest that blocking the NF-kappaB pathway might prevent cytokine-induced beta cell impairment as a means of facilitating islet transplantation.
Giannoukakis
N
N
Departments of Molecular Genetics and Biochemistry and of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Rudert
W A
WA
Trucco
M
M
Robbins
P D
PD
D000256:Adenoviridae; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000494:pharmacology; D005822:Genetic Vectors; D006801:Humans; D020672:I-kappa B Proteins; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide