Dendritic Cells from Nonobese Diabetic Mice Exhibit a Defect in NF-κB Regulation Due to a Hyperactive IκB Kinase

Abstract

Insulin-dependent diabetes mellitus (IDDM) is characterized by the T cell-mediated destruction of insulin-producing β cells. Accordingly, APCs, such as macrophage, have also been shown to be important in the disease process. However, the role(s) of dendritic cells (DCs) that exhibit potent APC function remains undefined in IDDM. Here we demonstrate that DCs derived from nonobese diabetic (NOD) mice, a model for IDDM, are more sensitive to various forms of stimulation compared with those from C57BL/6 and BALB/c mice, resulting in increased IL-12 secretion. This property is a consequence of hyperactivation of NF-κB, a transcription factor known to regulate IL-12 gene expression. Specifically, NOD DCs exhibit persistent hyperactivation of both IκB kinase and NF-κB in response to stimuli, in addition to selective degradation of IκBε. Transfection of NOD DCs with a modified form of IκBα significantly reduced IL-12 secretion, suggesting that hyperactivation of NF-κB was in part responsible for increased IL-12 production. An enhanced capacity of NOD DCs to secrete IL-12 would be expected to contribute to the development of pathogenic Th1 (Tc1) cells during the diabetogenic response.

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.…”

Aberrant Production of IL-12 by Macrophages from Several Autoimmune-Prone Mouse Strains Is Characterized by Intrinsic and Unique Patterns of NF-κB Expression and Binding to the IL-12 p40 Promoter

“…Recently, NF-B defects (specifically, reduced levels of p65) have been reported in T cells from lupus patients (21). Additionally, it has been shown that NOD dendritic cells overexpress B/ Rel as a consequence of enhanced function of I B kinase (22). In distinction to our findings, the latter group reported an increase in both hetero-and homodimer binding using a consensus MHC I NF-B sequence rather than a specific IL-12 p40 B sequence as used here.…”

NF-κB and the regulation of hematopoiesis

“…IKKs hyperactivity has been demonstrated to be responsible for elevated NF-kB activation in NOD mouse DCs and the subsequent increase of IL-12 production in these mice. 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.…”