Elevated NF-κB 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-κB activation upon stimulation. In the current study, we investigated the influence of dysregulation of NF-κB 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 IκBα, indicating a direct role for NF-κB 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-κB 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-κB activation, secretion of IL-12(p70) and TNF-α, and the capacity to stimulate T cells. Therefore, elevated NF-κB 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-κB in regulating the APC function of DC.

Functional variants in SUMO4, TAB2, and NFκB and the risk of type 1 diabetes

“…26 Studies in the NOD mouse that report altered levels of NFkB activity have typically reported cited post-translational effects as the primary cause. [21][22][23] The discordant findings for the role of the TAB2/ SUMO4 region in T1D, arising in three independent studies (the original reports of Owerbach et al and Guo et al, as well as the current study), are difficult to interpret. Each of the studies is internally consistent insofar as each finds significant pairwise linkage disequilibrium between the markers genotyped in the region.…”

“…19,20 As alterations in NFkB activity have been implicated in the etiology of diabetes in the NOD mouse model, a gene whose product can modulate NFkB activity is a potentially interesting candidate. [21][22][23] The TAB2/SUMO4 locus maps within the region that has been designated as IDDM5 based on prior linkage studies in ASP families. 18 Two independent studies genotyped overlapping 300 and 320 kb intervals in the IDDM5 region with 18 and 15 SNP markers, respectively.…”

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

“…DC precursors in BM of NOD mice and BB-DP rats also show proliferation/differentiation abnormalities and from these precursors abnormal ''steady state'' DCs arise with a spontaneous high pro-inflammatory set point [29,30]. These abnormal DCs have a high level of NF-kB and a high acid phosphatase, high IL-12 and low IL-10 expression [31][32][33][34]. These DCs are incapable of sufficiently sustaining the proliferation of Treg-cell populations in the NOD mouse and BB-DP rat [35,36].…”

NF-κB and the regulation of hematopoiesis

“…73 The same group showed that hyperactivation of NF-kB results in enhanced APC presentation. 74 The importance of NF-kB and DCs in diabetes has recently been confirmed, since in vivo administration of DCs in which NF-kB was blocked prevents the development of diabetes in NOD mice. 75 Although type 2 diabetes is characterized by peripheral insulin resistance, it has been hypothesized that obesity, inflammation and type 2 diabetes could be linked.…”