IL-1 receptor-associated kinase 4 is essential for IL-18-mediated NK and Th1 cell responses

Nobutaka Suzuki, Nien Jung Chen, Douglas G. Millar, Shinobu Suzuki, Thomas Horacek, Hiromitsu Hara, Denis Bouchard, Kenji Nakanishi, Josef M. Penninger, Pamela S. Ohashi, Wen Chen Yeh

    Research output: Contribution to journalArticlepeer-review


    IL-18 is an important cytokine for both innate and adaptive immunity. NK T cells and Th1 cells depend on IL-18 for their divergent functions. The IL-18R, IL-1R, and mammalian Toll-like receptors (TLRs) share homologous intracellular domains known as the TLR/IL-1R/plant R domain. Previously, we reported that IL-1R-associated kinase (IRAK)-4 plays a critical role in IL-1R and TLR signaling cascades and is essential for the innate immune response. Because TLR/IL-1R/plant R-containing receptors mediate signal transduction in a similar fashion, we investigated the role of IRAK-4 in IL-18R signaling. In this study, we show that IL-18-induced responses such as NK cell activity, Th1 IFN-γ production, and Th1 cell proliferation are severely impaired in IRAK-4-deficient mice. IRAK-4 -/- Th1 cells also do not exhibit NF-κB activation or IκB degradation in response to IL-18. Moreover, AP-1 activation which is triggered by c-Jun N-terminal kinase activation is also completely inhibited in IRAK-4 -/- Th1 cells. These results suggest that IRAK-4 is an essential component of the IL-18 signaling cascade.
    Original languageEnglish
    Pages (from-to)4031-4035
    Number of pages4
    JournalJournal of Immunology
    Issue number8
    Publication statusPublished - 15 Apr 2003


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