title: Improved intraportal islet transplantation outcome by systemic IKK-beta inhibition: NF-κB activity in pancreatic islets depends on oxygen availability.
abstract: Intraportal islet transplantation suffers from low efficiency caused by substantial islet mass loss after transplantation. How this process is regulated is still unclear. Here, we show that NF-κB activation was detectable in islet grafts shortly after transplantation of porcine islets to diabetic NMRI nu/nu mice, and systemic NF-κB inhibition in transplanted animals significantly prolonged islet graft survival. Proinflammatory cytokines alone did not cause evident cell death in pancreatic islet within 24 h, while the combination of cytokines with hypoxia resulted in a strong induction of cell death that could be blocked dose-dependently by a selective IKK-β inhibitor. Under hypoxia, NF-κB activity impaired expression of antiapoptotic gene BCL-xL, c-FLIP and survivin. NF-κB activation in isolated islets was reduced by hypoxia in a time-dependent manner, accordingly, NF-κB activation in transplanted islets diminished by time. Our data indicate that, while NF-κB has an antiapoptotic role under normoxia, low oxygen conditions decrease its activity and transform it to a proapoptotic transcription factor in pancreatic islets. We conclude that NF-κB inhibition represents a potential strategy to improve islet transplantation efficiency.
authors.affiliation: Third Medical Department Institute of Biochemistry, Medical Faculty, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Moreno
authors.forename: B
authors.initials: B
authors.lastname: Samikannu
authors.forename: R G
authors.initials: RG
authors.lastname: Bretzel
authors.forename: M L
authors.initials: ML
authors.lastname: Schmitz
authors.forename: T
authors.initials: T
authors.lastname: Linn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000379:methods* / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011169:Portal Vein; D011810:Quinoxalines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D016207:Cytokines; D007093:Imidazoles; D016328:NF-kappa B; D011810:Quinoxalines; D011994:Recombinant Proteins; D051550:I-kappa B Kinase; D010100:Oxygen