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B Regulation Due to a Hyperactive IB Kinase1
,
,,,*
*
Department of Microbiology and Immunology, School of Medicine;
Department of Biology,
Lineberger Comprehensive Cancer Center, and
Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599
Insulin-dependent diabetes mellitus (IDDM) is characterized by the
T cell-mediated destruction of insulin-producing 
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-
B, a transcription factor known to regulate
IL-12 gene expression. Specifically, NOD DCs exhibit persistent
hyperactivation of both IB kinase and NF-B in response to
stimuli, in addition to selective degradation of IB
. Transfection
of NOD DCs with a modified form of IB
significantly reduced IL-12
secretion, suggesting that hyperactivation of NF-B 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.
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