title: Elevated NF-kappaB activation in nonobese diabetic mouse dendritic cells results in enhanced APC function.
abstract: We have recently demonstrated that dendritic cells (DC) prepared from nonobese diabetic (NOD) mice, a spontaneous model for insulin-dependent diabetes mellitus, exhibit elevated levels of NF-kappaB activation upon stimulation. In the current study, we investigated the influence of dysregulation of NF-kappaB activation on the APC function of bone marrow-derived DC prepared from NOD vs BALB/c and nonobese diabetes-resistant mice. NOD DC pulsed with either peptide or virus were found to be more efficient than BALB/c DC at stimulating in vitro naive Ag-specific CD8+ T cells. The T cell stimulatory capacity of NOD DC was suppressed by gene transfer of a modified form of IkappaBalpha, indicating a direct role for NF-kappaB in this process. Furthermore, neutralization of IL-12(p70) to block autocrine-mediated activation of DC also significantly reduced the capacity of NOD DC to stimulate T cells. Despite a reduction in low molecular mass polypeptide-2 expression relative to BALB/c DC, no effect on proteasome-dependent events associated with the NF-kappaB signaling pathway or Ag processing was detected in NOD DC. Finally, DC from nonobese diabetes-resistant mice, a strain genotypically similar to NOD yet disease resistant, resembled BALB/c and not NOD DC in terms of the level of NF-kappaB activation, secretion of IL-12(p70) and TNF-alpha, and the capacity to stimulate T cells. Therefore, elevated NF-kappaB activation and enhanced APC function are specific for the NOD genotype and correlate with the progression of insulin-dependent diabetes mellitus. These results also provide further evidence indicating a key role for NF-kappaB in regulating the APC function of DC.
authors.affiliation: Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Poligone
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Weaver
authors.forename: Pradip
authors.initials: P
authors.lastname: Sen
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Roland
authors.initials: R
authors.lastname: Tisch
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000276:immunology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D020672:I-kappa B Proteins; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009975:Orthomyxoviridae / Q000276:immunology; D010455:Peptides / Q000276:immunology; D014176:Protein Biosynthesis; D013045:Species Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000906:Antibodies; D000956:Antigens, Viral; D016207:Cytokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D010455:Peptides; D000072000:NF-KappaB Inhibitor alpha; C071313:LMP-2 protein; D018664:Interleukin-12; D003546:Cysteine Endopeptidases