IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9.
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.
Hoshino
Katsuaki
K
Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Suehiro-cho 1-7-22, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Sugiyama
Takahiro
T
Matsumoto
Mitsuru
M
Tanaka
Takashi
T
Saito
Masuyoshi
M
Hemmi
Hiroaki
H
Ohara
Osamu
O
Akira
Shizuo
S
Kaisho
Tsuneyasu
T
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000096:biosynthesis*; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D016898:Interferon-alpha; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051550:I-kappa B Kinase