Protection of human islets from the effects of interleukin-1β by adenoviral gene transfer of an IκB repressor

Interleukin-1 beta (IL-1 beta) is a pro-inflammatory cytokine that inhibits beta cell function and promotes Fas-triggered apoptosis. IL-IP is thought to act early in the initiation of the autoimmune destruction of pancreatic beta cells in type I diabetes. IL-1 beta promotes beta cell impairment, in part, by activating NF-KB transcription factor-dependent signaling pathways. We have examined whether beta cells could be protected from the effects of IL-1 beta by overexpressing an inhibitor of NF-kappaB activity, I kappaB alpha 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 I kappaB alpha resulted in normal insulin responses to glucose in the presence of IL-1 beta. Furthermore, nitric oxide production was prevented and, more importantly, Fas-triggered apoptosis was inhibited following I kappaB alpha gene transfer. These results suggest that blocking the NF-KB pathway might prevent cytokine-induced beta cell impairment as a means of facilitating islet transplantation.