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    A Novel IRAK1–IKKԑ Signaling Axis Limits the Activation of TAK1–IKKb Downstream of TLR3


    Bruni, Daniela and Sebastia, Jordi and Dunne, Susan and Schroeder, Martina and Butler, Marion P. (2013) A Novel IRAK1–IKKԑ Signaling Axis Limits the Activation of TAK1–IKKb Downstream of TLR3. Journal of Immunology, 190. pp. 2844-2856. ISSN 0022-1767

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    Abstract

    IRAK1 is involved in the regulation of type I IFN production downstream of TLR3. Previous work indicated that IRAK1 negatively regulates TRIF-mediated activation of IRF3 and IRF7. We report that IRAK1 limits the activation of the TLR3–NF-кB pathway. Following TLR3 stimulation, IRAK1-deficient macrophages produced increased levels of IL-6 and IFN-β compared with wild type macrophages. Pharmacological inhibition of TAK1 reduced this increase in IFN-β, together with the heightened activation of IRF3 and p65 found in TLR3-ligand stimulated IRAK1-deficient macrophages. Recently, IKKԑ and TANK-binding kinase 1 (TBK1) were reported to limit activation of the NF-kB pathway downstream of IL-1R, TNFR1, and TLRs. We show that TBK1 has a positive role in the TLR3–NF-кB pathway, because we detected reduced levels of IL-6 and reduced activation of p65 in TBK1-deficient macrophages. In contrast, we show that IKK limits the activation of the TLR3–NF-кB pathway. Furthermore, we show that IRAK1 is required for the activation of IKK« downstream of TLR3. We report impaired activation of ERK1/2 in IRAK1– and IKKԑ-deficient macrophages, a novel finding for both kinases. Importantly, this work provides novel mechanistic insight into the regulation of the TLR3-signaling pathway, providing strong evidence that an IRAK1-IKKԑ–signaling axis acts to limit the production of both type I IFNs and proinflammatory cytokines by regulating TAK1 activity.

    Item Type: Article
    Keywords: IRAK1–IKKԑ; Signaling; Axis; Activation; TAK1–IKKb; Downstream; TLR3; Institute of Immunology; bone marrow–derived macrophage; kinase;
    Academic Unit: Faculty of Science and Engineering > Biology
    Faculty of Science and Engineering > Research Institutes > Institute of Immunology
    Item ID: 5414
    Depositing User: Martina Schroeder
    Date Deposited: 24 Sep 2014 13:50
    Journal or Publication Title: Journal of Immunology
    Publisher: American Association of Immunology
    Refereed: Yes
    URI:

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