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IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9

Abstract

The Toll-like receptor (TLR) family has important roles in microbial recognition and dendritic cell activation1,2. TLRs 7 and 9 can recognize nucleic acids3,4,5,6 and trigger signalling cascades that activate plasmacytoid dendritic cells to produce interferon-α (IFN-α) (refs 7, 8). TLR7/9-mediated dendritic cell activation is critical for antiviral immunity but also contributes to the pathogenesis of systemic lupus erythematosus, a disease in which serum IFN-α levels are elevated owing to plasmacytoid dendritic cell activation8,9. TLR7/9-induced IFN-α induction depends on a molecular complex that contains a TLR adaptor, MyD88, and IFN regulatory factor 7 (IRF-7) (refs 10–14), but the underlying molecular mechanisms are as yet unknown. Here we show that IκB kinase-α (IKK-α) is critically involved in TLR7/9-induced IFN-α production. TLR7/9-induced IFN-α production was severely impaired in IKK-α-deficient plasmacytoid dendritic cells, whereas inflammatory cytokine induction was decreased but still occurred. Kinase-deficient IKK-α inhibited the ability of MyD88 to activate the Ifna promoter in synergy with IRF-7. Furthermore, IKK-α associated with and phosphorylated IRF-7. Our results identify a role for IKK-α in TLR7/9 signalling, and highlight IKK-α as a potential target for manipulating TLR-induced IFN-α production.

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Figure 1: Role for IKK-α in IFN-α production from TLR7/9-stimulated BMDCs in vitro.
Figure 2: Impairment of TLR7/9-induced IFN-α production in Ikka -/- PDCs.
Figure 3: Role for IKK-α in IRF-7-mediated signalling.
Figure 4: IRF-7 phosphorylation and activation by IKK-α.

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Acknowledgements

We thank N. Iwami, Y. Fukuda, N. Okita and E. Haga for technical assistance; Y. Hachiman and H. Fujimoto for cell sorting; and S. Haraguchi and T. Oyanagi for secretarial assistance. We also thank R. Triendl for critical review of the manuscript. This work was supported by the Advanced and Innovational Research Program in Life Sciences, the Special Coordination Fund for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Grant-in-Aid for Scientific Research of MEXT and the Japan Society for the Promotion of Science, the Uehara Memorial Foundation, the Naito Foundation, the Novartis Foundation for the Promotion of Science, and RIKEN Strategic programs. T.S. is supported by a RIKEN Junior Research Associate grant.

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Correspondence to Tsuneyasu Kaisho.

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Hoshino, K., Sugiyama, T., Matsumoto, M. et al. IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9. Nature 440, 949–953 (2006). https://doi.org/10.1038/nature04641

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