Transcriptional regulation of type I diabetes by NF-kappa B.
Development of type I diabetes requires coordinated expression of myriad genes responsible for the initiation and progression of the disease. Expression of these genes are regulated by a small number of transcription factors including the Rel/NF-kappaB family. To determine the roles of the Rel/NF-kappaB family in type I diabetes, we studied multiple low-dose streptozotocin-induced diabetes in mice deficient in either c-Rel or NF-kappaB1. We found that mice deficient in each of these NF-kappaB subunits were resistant to streptozotocin-induced diabetes. However, the mechanisms of the disease resistance may differ in different cases. Deficiency in c-Rel selectively reduced Th1, but not Th2 responses, whereas NF-kappaB1 deficiency had little effect on T cell responses to anti-CD3 stimulation. Death of dendritic cells was accelerated in the absence of NF-kappaB1, whereas death of macrophages and granulocytes was affected primarily by c-Rel deficiency. Furthermore, Stat-1 expression was significantly reduced in macrophages deficient in NF-kappaB1, but not c-Rel. These results indicate that both c-Rel and NF-kappaB1are essential for the development of type I diabetes and that strategies targeting each of these subunits would be effective in preventing the disease.
Lamhamedi-Cherradi
Salah-Eddine
SE
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Zheng
Shijun
S
Hilliard
Brendan A
BA
Xu
Lingyun
L
Sun
Jing
J
Alsheadat
Saaib
S
Liou
Hsiou-Chi
HC
Chen
Youhai H
YH
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013311:Streptozocin / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000276:immunology*
D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D013311:Streptozocin; D007371:Interferon-gamma