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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


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 pages5
JournalJournal of Immunology
Issue number8
StatePublished - 15 Apr 2003


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