The role of nuclear factor-kappa B in beta-cell survival and function

In Type 1 diabetes, beta-cells is subjected to an autoimmune-mediated apoptoticand inflammatory attack. Whilst lymphocytes are the primary contributor of beta-celldeath, exposure of beta-cells to stress signals such as cytokines, transform these cellsinto an inflammatory state activating transcripts for toxic agents. Demonstrating asignificant role for beta-cells in participating in their own destruction through theelaboration of toxins and chemotactic molecules that could contribute to increasedcellular infiltration.The Nuclear Factor-kappa B (NF-kB) is a transcription factor that provides forearly immediate stress responses governing inflammation and cell survival. In islets,NF-kB is thought to have an important role in beta-cell inflammation and apoptosis. Fewstudies however, have explored the role of NF-kB in beta-cell protection. Indeed, wefound that the expression NF-kB is responsible for the islet-intrinsic immediate-earlypro-inflammatory gene expression. Importantly however, we also found that in islets,NF-kB is responsible for the expression and regulation of anti-apoptotic genes. Wedemonstrated for the first time that similar to other cells, the expression andregulation of the anti-inflammatory/ anti-apoptotic gene A20, in islets, is regulated byNF-kB.Consequently, we found a somewhat paradoxical role for NF-kB, where on theone hand it is responsible for beta-cell death, whilst on the other hand it is alsoresponsible for beta-cell survival. In vivo however, we found that islet survival andfunction was severely impaired in the absence of NF-kB activity. We observed thatblockade of NF-kB abrogate cytokine-induced A20 expression, and inhibited theactivation of glucose-stimulated insulin secretion in vitro. In contrast, blockade ofNF-kB by over-expression of A20 resulted in an improved islet allograft survival withgood metabolic control. Thus demonstrating the importance of NF-kB-dependentanti-apoptotic genes for islet survival and function.The findings presented in this thesis demonstrate a fundamental bimodal rolefor NF-kB in maintaining the balance of survival of beta-cells in the context of T1D.These data, uncovers a sophisticated molecular mechanism in the regulation of beta-celldeath, survival, and metabolic function. Thus providing a better understanding of therole of NF-kB in beta-cells in the context of T1D