Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction

Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-α in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7 signaling pathway. IRAK-1 directly bound and phosphorylated IRF7 in vitro. The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7. TLR7- and TLR9-mediated IFN-α production was abolished in Irak-1–deficient mice, whereas inflammatory cytokine production was not impaired. Despite normal activation of NF-κB and mitogen-activated protein kinases, IRF7 was not activated by a TLR9 ligand in Irak-1–deficient pDCs. These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-α induction in pDCs.

• Publication year

  2005

• Venue

  Journal of Experimental Medicine

• Publication date

  2005-03-21

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/jem.20042372PMID 15767370PMCID 2213113
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Toll-like receptors.

  2005cited by this paper
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  2004influential reference
• Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9.

  2004cited by this paper
• Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways.

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  2003cited by this paper
• Regulation of dendritic cell function through toll-like receptors.

  2003cited by this paper
• Toll-like receptors.

  2003cited by this paper
• Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4

  2003influential reference
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  2003influential reference
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  2003cited by this paper
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  2000cited by this paper
• Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction.

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• Article

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  2000cited by this paper
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• Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase.

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