A biphasic role of nuclear transcription factor (NF)-kappaB in the islet beta-cell apoptosis induced by interleukin (IL)-1beta.
IL-1beta 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 beta-cell apoptosis. Most of the IL-1beta effects seem to be mediated by NF-kappaB 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-kappaB activation, we studied the role of NF-kappaB in the rIL-1beta treated rat pancreatic islets. Our results show that TPCK blocked rIL-1beta-mediated early increase of MnSOD activity and beta-cell defence/repair protein expression, suggesting a protective role for NF-kappaB at the beginning of IL-1beta treatment; but, in a second phase, NF-kappaB 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-1beta treatment islet beta-cells begin to undergo apoptosis. Since IL-1beta induction of apoptosis is completely prevented by TCPK treatment, this finding underscores the central role of NF-kappaB in this process. Thus, our results clearly indicate that NF-kappaB regulates MnSOD genes expression and MnSOD activity, which protects islet beta-cells by IL-1beta damage. Furthermore, when the IL-1beta stress impairs islet beta-cell function, NF-kappaB activation regulates the entrance of islet beta-cell into the cell death program.
Papaccio
Gianpaolo
G
Department of Experimental Medicine, Laboratory of Histology and Embriology, 2nd University of Naples, Naples, Italy. gianpaolo.papaccio@unina2.it
Graziano
Antonio
A
D'Aquino
Riccardo
R
Valiante
Salvatore
S
Naro
Fabio
F
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D008933:Mitochondrial Swelling / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology
D007328:Insulin; D007375:Interleukin-1; D016328:NF-kappa B; D009573:Nitrites; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D014108:Tosylphenylalanyl Chloromethyl Ketone; D013482:Superoxide Dismutase; D000154:Aconitate Hydratase