Dendritic cells from nonobese diabetic mice exhibit a defect in NF-kappa Bregulation due to a hyperactive I kappa B kinase

Insulin-dependent diabetes mellitus (IDDM) is characterized by the T cell-m ediated destruction of insulin-producing beta cells. Accordingly, APCs, suc h as macrophage, have also been shown to be important in the disease proces s. However, the role(s) of dendritic cells (DCs) that exhibit potent APC fu nction remains undefined in IDDM. Here we demonstrate that DCs derived from nonobese diabetic (NOD) mice, a model for IDDM, are more sensitive to vari ous 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 h yperactivation of NF-KB, a transcription factor known to regulate IL-12 gen e expression. Specifically, NOD DCs exhibit persistent hyperactivation of b oth I kappaB kinase and NF kappaB in response to stimuli, in addition to se lective degradation of I kappaB epsilon. Transfection of NOD DCs with a mod ified form of I kappaB alpha significantly reduced IL-12 secretion, suggest ing that hyperactivation of NF-kappaB was in part responsible for increased IL-12 production. An enhanced capacity of NOD DCs to secrete IL-12 would b e expected to contribute to the development of pathogenic Th1 (Tc1) cells d uring the diabetogenic response.