Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents.
Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta cells. Islet-infiltrating leukocytes secrete cytokines such as IL-1beta and IFN-gamma, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-kappaB is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-kappaB in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-kappaB protein inhibitor (DeltaNIkappaBalpha), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the DeltaNIkappaBalpha protein were resistant to the deleterious effects of IL-1beta and IFN-gamma, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo, where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-kappaB is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.
Eldor
R
R
Department of Endocrinology, Hadassah University Hospital, Jerusalem 91120, Israel.
Yeffet
A
A
Baum
K
K
Doviner
V
V
Amar
D
D
Ben-Neriah
Y
Y
Christofori
G
G
Peled
A
A
Carel
J C
JC
Boitard
C
C
Klein
T
T
Serup
P
P
Eizirik
D L
DL
Melloul
D
D
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines; D004247:DNA / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004318:Doxycycline / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D013311:Streptozocin / Q000494:pharmacology; D046509:Tissue Culture Techniques
D016207:Cytokines; D007375:Interleukin-1; D016328:NF-kappa B; D013311:Streptozocin; D007371:Interferon-gamma; D004247:DNA; D051550:I-kappa B Kinase; D004318:Doxycycline