Abstract
IL‐1β is an important mediator in the pathogenesis of type 1 diabetes both in vivo and in vitro and it has been shown to induce islet β‐cell apoptosis. Most of the IL‐1β effects seem to be mediated by NF‐κB transcription factor activation, but its role in the induction of islet β‐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‐κB activation, we studied the role of NF‐κB in the rIL‐1β treated rat pancreatic islets. Our results show that TPCK blocked rIL‐1β‐mediated early increase of MnSOD activity and β‐cell defence/repair protein expression, suggesting a protective role for NF‐κB at the beginning of IL‐1β treatment; but, in a second phase, NF‐κB induces a sustained decrease of specific β‐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‐1β treatment islet β‐cells begin to undergo apoptosis. Since IL‐1β induction of apoptosis is completely prevented by TCPK treatment, this finding underscores the central role of NF‐κB in this process. Thus, our results clearly indicate that NF‐κB regulates MnSOD genes expression and MnSOD activity, which protects islet β‐cells by IL‐1β damage. Furthemore, when the IL‐1β stress impairs islet β‐cell function, NF‐κB activation regulates the entrance of islet β‐cell into the cell death program. © 2004 Wiley‐Liss, Inc.