Abstract
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.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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DNA-Binding Proteins / biosynthesis
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Diabetes Mellitus, Experimental / genetics
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Diabetes Mellitus, Experimental / immunology
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Type 1 / genetics*
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / pathology
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Dose-Response Relationship, Immunologic
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Immunity, Innate / genetics
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Interferon-gamma / pharmacology
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Lipopolysaccharides / pharmacology
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Lymphocyte Activation / genetics
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Cells / cytology
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Myeloid Cells / immunology
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Myeloid Cells / metabolism
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Myeloid Cells / pathology
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NF-kappa B / deficiency
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NF-kappa B / genetics
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NF-kappa B / physiology*
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NF-kappa B p50 Subunit
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Proto-Oncogene Proteins c-rel / deficiency
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Proto-Oncogene Proteins c-rel / genetics
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Proto-Oncogene Proteins c-rel / physiology
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STAT1 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology
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Streptozocin / administration & dosage
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / pathology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th1 Cells / pathology
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Trans-Activators / biosynthesis
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Transcription, Genetic / immunology*
Substances
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DNA-Binding Proteins
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Lipopolysaccharides
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NF-kappa B
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NF-kappa B p50 Subunit
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Proto-Oncogene Proteins c-rel
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STAT1 Transcription Factor
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Stat1 protein, mouse
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Trans-Activators
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Streptozocin
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Interferon-gamma