Essential Role for IKKβ in Production of Type 1 Interferons by Plasmacytoid Dendritic Cells*

Background: The role of IKKβ in the production of type 1 interferons by plasmacytoid dendritic cells (pDCs) is unknown. Results: Inhibition of IKKβ and its activator TAK1 prevents the production of IFNβ in pDCs, and hence the production of IFNα. Conclusion: Toll-like receptor 7/9-stimulated production of interferons in pDCs requires the canonical IKKs and TAK1. Significance: IKKβ inhibitors may have potential for the treatment of autoimmunity. Plasmacytoid dendritic cells (pDCs) are characterized by their ability to produce high levels of type 1 interferons in response to ligands that activate TLR7 and TLR9, but the signaling pathways required for IFN production are incompletely understood. Here we exploit the human pDC cell line Gen2.2 and improved pharmacological inhibitors of protein kinases to address this issue. We demonstrate that ligands that activate TLR7 and TLR9 require the TAK1-IKKβ signaling pathway to induce the production of IFNβ via a pathway that is independent of the degradation of IκBα. We also show that IKKβ activity, as well as the subsequent IFNβ-stimulated activation of the JAK-STAT1/2 signaling pathway, are essential for the production of IFNα by TLR9 ligands. We further show that TLR7 ligands CL097 and R848 fail to produce significant amounts of IFNα because the activation of IKKβ is not sustained for a sufficient length of time. The TLR7/9-stimulated production of type 1 IFNs is inhibited by much lower concentrations of IKKβ inhibitors than those needed to suppress the production of NFκB-dependent proinflammatory cytokines, such as IL-6, suggesting that drugs that inhibit IKKβ may have a potential for the treatment of forms of lupus that are driven by self-RNA and self-DNA-induced activation of TLR7 and TLR9, respectively.