Toll-Like Receptor 9 Signaling Activates NF-KB through IFN Regulatory Factor-8/IFN Consensus Sequence Binding Protein in Dendritic Cells

摘要

Unmethylated CpG DNA binds to the Toll-like receptor 9(TLR9)and activates NF-KB 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-alpha and IL-6,targets of NF-KB.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-KB in -/- cells.This was due to the selective inability of-/-DCs to activate I-kB kinase alpha beta,the kinases required for NF-KB in response to CpG.IRF-8 reintroduction fully restored CpG activation of NF-kB and cytokine induction in -/- DCs.Together,TLR signals that activate NF-KB are diverse among different TLRs,and TLR9 signaling uniquely depends on IRF-8 in DCs.