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

Katsuaki Hoshino, Takahiro Sugiyama, Mitsuru Matsumoto, Takashi Tanaka, Masuyoshi Saito, Hiroaki Hemmi, Osamu Ohara, Shizuo Akira and Tsuneyasu Kaisho ()
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Katsuaki Hoshino: Laboratory for Host Defense
Takahiro Sugiyama: Laboratory for Host Defense
Mitsuru Matsumoto: University of Tokushima
Takashi Tanaka: Laboratory for Host Defense
Masuyoshi Saito: Laboratory for Host Defense
Hiroaki Hemmi: Japan Science and Technology Agency
Osamu Ohara: RIKEN Research Center for Allergy and Immunology
Shizuo Akira: Japan Science and Technology Agency
Tsuneyasu Kaisho: Laboratory for Host Defense

Nature, 2006, vol. 440, issue 7086, 949-953

Abstract: 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.

Date: 2006
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DOI: 10.1038/nature04641

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