IRF-5 and NF-{kappa}B p50 co-regulate IFN-{beta} and IL-6 expression in TLR9-stimulated human plasmacytoid dendritic cells (P1363)

Robust production of type I interferon (IFN) by plasmacytoid dendritic cells (pDCs) occurs in response to Toll-like receptor 9 (TLR9) activation by unmethylated CpG dinucleotides present in bacterial and viral DNA. Previous work using different CpG oligodeoxynucleotides (ODN) revealed that CpG-A ODN but not CpG-B ODN robustly induce IFN-α production in pDCs. Although CpG-B ODN do not efficiently induce IFN-α, they are capable of highly inducing IFN-β. However, it is currently unclear what factors mediate CpG-B ODN induction of IFN-β in human pDCs. Using nuclear translocation, siRNA and proximity ligation assays, we demonstrate a requirement for both IRF-5 and NF-κB p50 in the induction of IFN-β and IL-6 by CpG-B ODN in human pDCs. The finding that CpG-B ODN activation of IRF-5 leads to IFN-β production in human pDCs may have clinical importance as IRF-5 has recently been identified as a major risk locus in systemic lupus erythematosus (SLE), a disease largely driven by aberrant type I IFN production by pDCs. Overall, this study provides new insights into the transcriptional regulation of IFN-β and IL-6 induced by CpG-B ODN in human pDCs and identifies a clinically important link between IRF-5 and IFN-β.