Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 3729K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kawagoe, T. Articles by Akira, S. Search for Related Content PubMed PubMed Citation Articles by Kawagoe, T. Articles by Akira, S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Social Bookmarking                            What's this?

¹ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
² Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Suita, Osaka 565-0871, Japan

CORRESPONDENCE Shizuo Akira: sakira{at}biken.osaka-u.ac.jp

Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor B (NF-B). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4^KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4^KN/KN as well as IRAK-4^–/– macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-B–regulated genes in response to TLR ligands such as tumor necrosis factor and IB. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4^–/– and IRAK-4^KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.

Abbreviations used: Ab, antibody; COX-2, cyclooxygenase-2; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal-regulated kinase; ES, embryonic stem; IKK-, IB kinase ; IL-1R, IL-1 receptor; IRAK, IL-1R–associated kinase; JNK, c-Jun N-terminal kinase; LCMV, lymphocytic choriomeningitis virus; MALP-2, macrophage-activating lipopeptide-2; MAP, mitogen-activated protein; MEF, mouse embryonic fibroblast; mRNA, messenger RNA; pDC, plasmacytoid DC; TIR, Toll/IL-1R; TLR, Toll-like receptor; TRAF6, TNF receptor–associated factor 6.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• de Vos, A. F., Pater, J. M., van den Pangaart, P. S., de Kruif, M. D., van 't Veer, C., van der Poll, T. (2009). In Vivo Lipopolysaccharide Exposure of Human Blood Leukocytes Induces Cross-Tolerance to Multiple TLR Ligands. J. Immunol. 183: 533-542 [Abstract] [Full Text]  
• Staschke, K. A., Dong, S., Saha, J., Zhao, J., Brooks, N. A., Hepburn, D. L., Xia, J., Gulen, M. F., Kang, Z., Altuntas, C. Z., Tuohy, V. K., Gilmour, R., Li, X., Na, S. (2009). IRAK4 Kinase Activity Is Required for Th17 Differentiation and Th17-Mediated Disease. J. Immunol. 183: 568-577 [Abstract] [Full Text]  
• Lu, Y.-C., Kim, I., Lye, E., Shen, F., Suzuki, N., Suzuki, S., Gerondakis, S., Akira, S., Gaffen, S. L., Yeh, W.-C., Ohashi, P. S. (2009). Differential Role for c-Rel and C/EBP{beta}/{delta} in TLR-Mediated Induction of Proinflammatory Cytokines. J. Immunol. 182: 7212-7221 [Abstract] [Full Text]  
• Fraczek, J., Kim, T. W., Xiao, H., Yao, J., Wen, Q., Li, Y., Casanova, J.-L., Pryjma, J., Li, X. (2008). The Kinase Activity of IL-1 Receptor-associated Kinase 4 Is Required for Interleukin-1 Receptor/Toll-like Receptor-induced TAK1-dependent NF{kappa}B Activation. J. Biol. Chem. 283: 31697-31705 [Abstract] [Full Text]  
• Conze, D. B., Wu, C.-J., Thomas, J. A., Landstrom, A., Ashwell, J. D. (2008). Lys63-Linked Polyubiquitination of IRAK-1 Is Required for Interleukin-1 Receptor- and Toll-Like Receptor-Mediated NF-{kappa}B Activation. Mol. Cell. Biol. 28: 3538-3547 [Abstract] [Full Text]  
• Kaczorowski, D. J., Mollen, K. P., Edmonds, R., Billiar, T. R. (2008). Early events in the recognition of danger signals after tissue injury. J. Leukoc. Biol. 83: 546-552 [Abstract] [Full Text]  
• Muroi, M., Tanamoto, K.-i. (2008). TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-{kappa}B. J. Leukoc. Biol. 83: 702-707 [Abstract] [Full Text]  
• Ku, C.-L., von Bernuth, H., Picard, C., Zhang, S.-Y., Chang, H.-H., Yang, K., Chrabieh, M., Issekutz, A. C., Cunningham, C. K., Gallin, J., Holland, S. M., Roifman, C., Ehl, S., Smart, J., Tang, M., Barrat, F. J., Levy, O., McDonald, D., Day-Good, N. K., Miller, R., Takada, H., Hara, T., Al-Hajjar, S., Al-Ghonaium, A., Speert, D., Sanlaville, D., Li, X., Geissmann, F., Vivier, E., Marodi, L., Garty, B.-Z., Chapel, H., Rodriguez-Gallego, C., Bossuyt, X., Abel, L., Puel, A., Casanova, J.-L. (2007). Selective predisposition to bacterial infections in IRAK-4 deficient children: IRAK-4 dependent TLRs are otherwise redundant in protective immunity. JEM 204: 2407-2422 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS