IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9

Nature. 2006 Apr 13;440(7086):949-53. doi: 10.1038/nature04641.


The Toll-like receptor (TLR) family has important roles in microbial recognition and dendritic cell activation. TLRs 7 and 9 can recognize nucleic acids and trigger signalling cascades that activate plasmacytoid dendritic cells to produce interferon-alpha (IFN-alpha) (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-alpha levels are elevated owing to plasmacytoid dendritic cell activation. TLR7/9-induced IFN-alpha 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 IkappaB kinase-alpha (IKK-alpha) is critically involved in TLR7/9-induced IFN-alpha production. TLR7/9-induced IFN-alpha production was severely impaired in IKK-alpha-deficient plasmacytoid dendritic cells, whereas inflammatory cytokine induction was decreased but still occurred. Kinase-deficient IKK-alpha inhibited the ability of MyD88 to activate the Ifna promoter in synergy with IRF-7. Furthermore, IKK-alpha associated with and phosphorylated IRF-7. Our results identify a role for IKK-alpha in TLR7/9 signalling, and highlight IKK-alpha as a potential target for manipulating TLR-induced IFN-alpha production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cells, Cultured
  • Cytokines / metabolism
  • Dendritic Cells / metabolism
  • I-kappa B Kinase / deficiency
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Interferon-alpha / biosynthesis*
  • Mice
  • Myeloid Differentiation Factor 88
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Toll-Like Receptor 7 / metabolism*
  • Toll-Like Receptor 9 / metabolism*
  • Up-Regulation


  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Interferon-alpha
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • I-kappa B Kinase