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B Hyperactivation Has Differential Effects on the APC Function of Nonobese Diabetic Mouse Macrophages1
* Department of Microbiology and Immunology, School of Medicine, and
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599
Type 1 diabetes is characterized by a chronic inflammatory response resulting in the selective destruction of the insulin-producing 
cells. We have previously demonstrated that dendritic cells (DCs) prepared from nonobese diabetic (NOD) mice, a model for spontaneous type 1 diabetes, exhibit hyperactivation of NF-
B resulting in an increased capacity to secrete proinflammatory cytokines and stimulate T cells compared with DCs of nondiabetic strains of mice. In the current study, the activational status of NF-B and its role in regulating the APC function of macrophages (M
) prepared from NOD, nonobese resistant (NOR), and BALB/c mice was investigated. Independent of the stimulus, splenic and bone marrow-derived M prepared from NOD mice exhibited increased NF-B activation relative to NOR and BALB/c M. This hyperactivation was detected for different NF-B complexes and correlated with increased IB
degradation. Furthermore, increased NF-B activation resulted in an enhanced capacity of NOD vs NOR or BALB/c M to secrete IL-12(p70), TNF-, and IL-1, which was inhibited upon infection with an adenoviral recombinant encoding a modified form of IB. In contrast, elevated NF-B activation had no significant effect on the capacity of NOD M to stimulate CD4+ or CD8+ T cells in an Ag-specific manner. These results demonstrate that in addition to NOD DCs, NOD M exhibit hyperactivation of NF-B, which correlates with an increased ability to mediate a proinflammatory response. Furthermore, NF-B influences M APC function by regulating cytokine secretion but not T cell stimulation.
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