A biphasic role of nuclear transcription factor (NF)-κB in the islet β-cell apoptosis induced by interleukin (IL)-1β

IL-1 beta is an important mediator in the pathogenesis of type I diabetes both in vivo and in vitro and it has been shown to induce islet beta-cell apoptosis. Most of the IL-1 beta effects seem to be mediated by NF-kappa B transcription factor activation, but its role in the induction of islet beta-cell apoptosis has not yet been clarified. Taking advantage of the protease inhibitor TPCK (N-tosyl-L-phenylalanine chloromethyl ketone), which specifically inhibits the nuclear transcription factor NF-kappa B activation, we studied the role of NF-kappa B in the rIL-1 beta treated rat pancreatic islets. Our results show that TPCK blocked rlL-1 beta-mediated early increase of MnSOD activity and beta-cell defence/repair protein expression, suggesting a protective role for NF-kappa B at the beginning of IL-1 beta treatment; but, in a second phase, NF-kappa B induces a sustained decrease of specific beta-cell proteins like insulin, GLUT-2 and PDX-1 with a concomitant increase of aspecific proteins and iNOS transcription. The appearance of iNOS expression correlates with increased levels of nitrite + nitrate levels and appearance of mitochondrial damage detected either at morphological and biochemical level. After 36 h of IL-1 beta treatment islet beta-cells begin to undergo apoptosis. Since IL-1 beta induction of apoptosis is completely prevented by TCPK treatment, this finding underscores the central role of NF-kappa B in this process. Thus, our results clearly indicate that NF-kappa B regulates MnSOD genes expression and MnSOD activity, which protects islet beta-cells by IL-1 beta damage. Furthermore, when the IL-1 beta stress impairs islet beta-cell function, NF-kappa B activation regulates the entrance of islet beta-cell into the cell death program.