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B through IFN Regulatory Factor-8/IFN Consensus Sequence Binding Protein in Dendritic Cells1
* Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and
Center for Biologics Evaluation Research, Food and Drug Administration, Bethesda, MD 20892
Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-
B to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN consensus sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8–/– mice were unresponsive to CpG and failed to induce TNF-
and IL-6, targets of NF-B. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8–/– DCs in response to LPS that signals through TLR4. IRF-8–/– DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-B in –/– cells. This was due to the selective inability of –/– DCs to activate I-B kinase 
, the kinases required for NF-B in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-B and cytokine induction in –/– DCs. Together, TLR signals that activate NF-B are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.
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