Role of NF-kappaB in beta-cell death.

Apoptotic beta-cell death appears to be central to the pathogenesis of Type 1 diabetes mellitus and in islet graft rejection. The beta-cell destruction is partially mediated by cytokines, such as IL-1beta (interleukin 1beta), TNFalpha (tumour necrosis factor alpha) and IFN-gamma (interferon gamma). IL-1beta and TNFalpha mediate activation of the transcription factor NF-kappaB (nuclear factor kappaB) pathway. Use of a degradation-resistant NF-kappaB protein inhibitor (DeltaNIkappaBalpha), specifically expressed in beta-cells, significantly reduced IL-1beta+IFN-gamma-induced apoptosis. Moreover, in vivo, it protected against multiple low-dose streptozocin-induced diabetes, with reduced intra-islet lymphocytic infiltration. Thus beta-cell-specific activation of NF-kappaB is a key event in the progressive loss of beta-cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.