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IL-1 Receptor-Associated Kinase 4 Is Essential for IL-18-Mediated NK and Th1 Cell Responses¹

Nobutaka Suzuki^*, Nien-Jung Chen^*, Douglas G. Millar, Shinobu Suzuki^*, Thomas Horacek^*, Hiromitsu Hara, Denis Bouchard^*, Kenji Nakanishi, Josef M. Penninger, Pamela S. Ohashi and Wen-Chen Yeh^2,*

^* Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, Ontario Cancer Institute and Departments of Medical Biophysics and Immunology, and University Health Network and Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; and Department of Immunology and Medical Zoology, Laboratory Host Defenses Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

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- production, and Th1 cell proliferation are severely impaired in IRAK-4-deficient mice. IRAK-4^-/- Th1 cells also do not exhibit NF-B activation or IB 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.

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