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

This Article Full Text Full Text (PDF, 244K) PPT slides of all figures 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 Kanakaraj, P. Articles by Fung-Leung, W.-P. Search for Related Content PubMed PubMed Citation Articles by Kanakaraj, P. Articles by Fung-Leung, W.-P. Social Bookmarking                            What's this?

Articles

Palanisamy Kanakaraj^*, Peter H. Schafer, Druie E. Cavender, Ying Wu^*, Karen Ngo^*, Patrick F. Grealish, Scott A. Wadsworth, Per A. Peterson, John J. Siekierka, Crafford A. Harris, and Wai-Ping Fung-Leung^*

From the ^* R.W. Johnson Pharmaceutical Research Institute, San Diego, California 92121; and the R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869

Interleukin (IL)-1 is a proinflammatory cytokine with pleiotropic effects in inflammation. IL-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (MAP) kinases, c-Jun NH₂-terminal kinase (JNK) and p38 MAP kinase, as well as transcription factor nuclear factor B (NF-B). IL-1 signaling results in cellular responses through induction of inflammatory gene products such as IL-6. One of the earliest events in IL-1 signaling is the rapid interaction of IL-1 receptor–associated kinases, IRAK and IRAK-2, with the receptor complex. The relative roles of IRAK and IRAK-2 in IL-1 signaling pathways and subsequent cellular responses have not been previously determined. To evaluate the importance of IRAK in IL-1 signaling, IRAK-deficient mouse fibroblast cells were prepared and studied. Here we report that IL-1–mediated activation of JNK, p38, and NF-B were all reduced in embryonic fibroblasts deficient in IRAK expression. In addition, IL-6 production in response to IL-1 was also dramatically reduced in IRAK-deficient embryonic fibroblasts and in skin fibroblasts prepared from IRAK-deficient mice. Our results demonstrate that IRAK plays an essential proximal role in coordinating multiple IL-1 signaling pathways for optimal induction of cellular responses.

Key Words: IRAK • IL-1 • JNK • p38 • NF-B

Abbreviations used: EF, embryonic fibroblast; IB, inhibitor of NF-B; IRAK, interleukin 1 receptor–associated kinase; JNK, c-Jun NH₂-terminal kinase; MAP, mitogen-activated protein kinase; MAPKAPK2, MAP kinase–activated protein kinase 2; NF-B, nuclear factor B; SF, skin fibroblast; TRAF, TNF receptor–associated factor.

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

This article has been cited by other articles:

• Ahmad, R., Sylvester, J., Ahmad, M., Zafarullah, M. (2009). Adaptor Proteins and Ras Synergistically Regulate IL-1-Induced ADAMTS-4 Expression in Human Chondrocytes. J. Immunol. 182: 5081-5087 [Abstract] [Full Text]  
• Mogensen, T. H. (2009). Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses. Clin. Microbiol. Rev. 22: 240-273 [Abstract] [Full Text]  
• Liu, G., Park, Y.-J., Abraham, E. (2008). Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-{kappa}B activation requires cytosolic and nuclear activity. FASEB J. 22: 2285-2296 [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]  
• Windheim, M., Stafford, M., Peggie, M., Cohen, P. (2008). Interleukin-1 (IL-1) Induces the Lys63-Linked Polyubiquitination of IL-1 Receptor-Associated Kinase 1 To Facilitate NEMO Binding and the Activation of I{kappa}B{alpha} Kinase. Mol. Cell. Biol. 28: 1783-1791 [Abstract] [Full Text]  
• Keating, S. E., Maloney, G. M., Moran, E. M., Bowie, A. G. (2007). IRAK-2 Participates in Multiple Toll-like Receptor Signaling Pathways to NF{kappa}B via Activation of TRAF6 Ubiquitination. J. Biol. Chem. 282: 33435-33443 [Abstract] [Full Text]  
• Kawagoe, T., Sato, S., Jung, A., Yamamoto, M., Matsui, K., Kato, H., Uematsu, S., Takeuchi, O., Akira, S. (2007). Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling. JEM 204: 1013-1024 [Abstract] [Full Text]  
• Ikeda, Y., Murakami, A., Fujimura, Y., Tachibana, H., Yamada, K., Masuda, D., Hirano, K.-i., Yamashita, S., Ohigashi, H. (2007). Aggregated Ursolic Acid, a Natural Triterpenoid, Induces IL-1beta Release from Murine Peritoneal Macrophages: Role of CD36. J. Immunol. 178: 4854-4864 [Abstract] [Full Text]  
• Lotz, M., Gutle, D., Walther, S., Menard, S., Bogdan, C., Hornef, M. W. (2006). Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. JEM 203: 973-984 [Abstract] [Full Text]  
• Sun, J., Wiklund, F., Hsu, F.-C., Balter, K., Zheng, S. L., Johansson, J.-E., Chang, B., Liu, W., Li, T., Turner, A. R., Li, L., Li, G., Adami, H.-O., Isaacs, W. B., Xu, J., Gronberg, H. (2006). Interactions of sequence variants in interleukin-1 receptor-associated kinase4 and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk.. Cancer Epidemiol. Biomarkers Prev. 15: 480-485 [Abstract] [Full Text]  
• Ohnuma, K., Yamochi, T., Uchiyama, M., Nishibashi, K., Iwata, S., Hosono, O., Kawasaki, H., Tanaka, H., Dang, N. H., Morimoto, C. (2005). CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells. Mol. Cell. Biol. 25: 7743-7757 [Abstract] [Full Text]  
• Rao, N., Nguyen, S., Ngo, K., Fung-Leung, W.-P. (2005). A Novel Splice Variant of Interleukin-1 Receptor (IL-1R)-Associated Kinase 1 Plays a Negative Regulatory Role in Toll/IL-1R-Induced Inflammatory Signaling. Mol. Cell. Biol. 25: 6521-6532 [Abstract] [Full Text]  
• Uematsu, S., Sato, S., Yamamoto, M., Hirotani, T., Kato, H., Takeshita, F., Matsuda, M., Coban, C., Ishii, K. J., Kawai, T., Takeuchi, O., Akira, S. (2005). Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. JEM 201: 915-923 [Abstract] [Full Text]  
• De Nardo, D., Masendycz, P., Ho, S., Cross, M., Fleetwood, A. J., Reynolds, E. C., Hamilton, J. A., Scholz, G. M. (2005). A Central Role for the Hsp90{middle dot}Cdc37 Molecular Chaperone Module in Interleukin-1 Receptor-associated-kinase-dependent Signaling by Toll-like Receptors. J. Biol. Chem. 280: 9813-9822 [Abstract] [Full Text]  
• Horton, J. W., Tan, J., White, D. J., Maass, D. L., Thomas, J. A. (2004). Selective decontamination of the digestive tract attenuated the myocardial inflammation and dysfunction that occur with burn injury. Am. J. Physiol. Heart Circ. Physiol. 287: H2241-H2251 [Abstract] [Full Text]  
• Lye, E., Mirtsos, C., Suzuki, N., Suzuki, S., Yeh, W.-C. (2004). The Role of Interleukin 1 Receptor-associated Kinase-4 (IRAK-4) Kinase Activity in IRAK-4-mediated Signaling. J. Biol. Chem. 279: 40653-40658 [Abstract] [Full Text]  
• Wheeler, D. S., Catravas, J. D., Odoms, K., Denenberg, A., Malhotra, V., Wong, H. R. (2004). Epigallocatechin-3-gallate, a Green Tea-Derived Polyphenol, Inhibits IL-1{beta}-Dependent Proinflammatory Signal Transduction in Cultured Respiratory Epithelial Cells. J. Nutr. 134: 1039-1044 [Abstract] [Full Text]  
• Zhang, Y., Chen, F. (2004). Reactive Oxygen Species (ROS), Troublemakers between Nuclear Factor-{kappa}B (NF-{kappa}B) and c-Jun NH2-terminal Kinase (JNK). Cancer Res. 64: 1902-1905 [Abstract] [Full Text]  
• Kobayashi, K. S., Flavell, R. A. (2004). Shielding the double-edged sword: negative regulation of the innate immune system. J. Leukoc. Biol. 75: 428-433 [Abstract] [Full Text]  
• Kollewe, C., Mackensen, A.-C., Neumann, D., Knop, J., Cao, P., Li, S., Wesche, H., Martin, M. U. (2004). Sequential Autophosphorylation Steps in the Interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling. J. Biol. Chem. 279: 5227-5236 [Abstract] [Full Text]  
• Okamoto, T., Gohil, K., Finkelstein, E. I., Bove, P., Akaike, T., van der Vliet, A. (2004). Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 286: L198-L209 [Abstract] [Full Text]  
• Suzuki, N., Suzuki, S., Eriksson, U., Hara, H., Mirtosis, C., Chen, N.-J., Wada, T., Bouchard, D., Hwang, I., Takeda, K., Fujita, T., Der, S., Penninger, J. M., Akira, S., Saito, T., Yeh, W.-C. (2003). IL-1R-Associated Kinase 4 Is Required for Lipopolysaccharide- Induced Activation of APC. J. Immunol. 171: 6065-6071 [Abstract] [Full Text]  
• Akira, S. (2003). Toll-like Receptor Signaling. J. Biol. Chem. 278: 38105-38108 [Full Text]  
• Thomas, J. A., Haudek, S. B., Koroglu, T., Tsen, M. F., Bryant, D. D., White, D. J., Kusewitt, D. F., Horton, J. W., Giroir, B. P. (2003). IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. Am. J. Physiol. Heart Circ. Physiol. 285: H597-H606 [Abstract] [Full Text]  
• Yeo, S.-J., Gravis, D., Yoon, J.-G., Yi, A.-K. (2003). Myeloid Differentiation Factor 88-dependent Transcriptional Regulation of Cyclooxygenase-2 Expression by CpG DNA: ROLE OF NF-{kappa}B AND p38. J. Biol. Chem. 278: 22563-22573 [Abstract] [Full Text]  
• Hobbs, R. M., Watt, F. M. (2003). Regulation of Interleukin-1{alpha} Expression by Integrins and Epidermal Growth Factor Receptor in Keratinocytes from a Mouse Model of Inflammatory Skin Disease. J. Biol. Chem. 278: 19798-19807 [Abstract] [Full Text]  
• Deng, C., Radu, C., Diab, A., Tsen, M. F., Hussain, R., Cowdery, J. S., Racke, M. K., Thomas, J. A. (2003). IL-1 Receptor-Associated Kinase 1 Regulates Susceptibility to Organ-Specific Autoimmunity. J. Immunol. 170: 2833-2842 [Abstract] [Full Text]  
• Burns, K., Janssens, S., Brissoni, B., Olivos, N., Beyaert, R., Tschopp, J. (2003). Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4. JEM 197: 263-268 [Abstract] [Full Text]  
• Yeo, S.-J., Yoon, J.-G., Hong, S.-C., Yi, A.-K. (2003). CpG DNA Induces Self and Cross-Hyporesponsiveness of RAW264.7 Cells in Response to CpG DNA and Lipopolysaccharide: Alterations in IL-1 Receptor-Associated Kinase Expression. J. Immunol. 170: 1052-1061 [Abstract] [Full Text]  
• Thomas, J. A., Tsen, M. F., White, D. J., Horton, J. W. (2002). IRAK contributes to burn-triggered myocardial contractile dysfunction. Am. J. Physiol. Heart Circ. Physiol. 283: H829-H836 [Abstract] [Full Text]  
• Chen, B.-C., Wu, W.-T., Ho, F.-M., Lin, W.-W. (2002). Inhibition of Interleukin-1beta -induced NF-kappa B Activation by Calcium/Calmodulin-dependent Protein Kinase Kinase Occurs through Akt Activation Associated with Interleukin-1 Receptor-associated Kinase Phosphorylation and Uncoupling of MyD88. J. Biol. Chem. 277: 24169-24179 [Abstract] [Full Text]  
• Mizel, S. B., Snipes, J. A. (2002). Gram-negative Flagellin-induced Self-tolerance Is Associated with a Block in Interleukin-1 Receptor-associated Kinase Release from Toll-like Receptor 5. J. Biol. Chem. 277: 22414-22420 [Abstract] [Full Text]  
• Li, S., Strelow, A., Fontana, E. J., Wesche, H. (2002). IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase. Proc. Natl. Acad. Sci. USA 99: 5567-5572 [Abstract] [Full Text]  
• Hu, J., Jacinto, R., McCall, C., Li, L. (2002). Regulation of IL-1 Receptor-Associated Kinases by Lipopolysaccharide. J. Immunol. 168: 3910-3914 [Abstract] [Full Text]  
• Vasselon, T., Hanlon, W. A, Wright, S. D, Detmers, P. A. (2002). Toll-like receptor 2 (TLR2) mediates activation of stress-activated MAP kinase p38. J. Leukoc. Biol. 71: 503-510 [Abstract] [Full Text]  
• McDermott, E. P., O'Neill, L. A. J. (2002). Ras Participates in the Activation of p38 MAPK by Interleukin-1 by Associating with IRAK, IRAK2, TRAF6, and TAK-1. J. Biol. Chem. 277: 7808-7815 [Abstract] [Full Text]  
• Silverman, N., Maniatis, T. (2001). NF-{kappa}B signaling pathways in mammalian and insect innate immunity. Genes Dev. 15: 2321-2342 [Full Text]  
• Alexander, C., Rietschel, E. Th. (2001). Invited review: Bacterial lipopolysaccharides and innate immunity. Innate Immunity 7: 167-202 [Abstract]  
• Takaesu, G., Ninomiya-Tsuji, J., Kishida, S., Li, X., Stark, G. R., Matsumoto, K. (2001). Interleukin-1 (IL-1) Receptor-Associated Kinase Leads to Activation of TAK1 by Inducing TAB2 Translocation in the IL-1 Signaling Pathway. Mol. Cell. Biol. 21: 2475-2484 [Abstract] [Full Text]  
• Haddad, J. J. E., Safieh-Garabedian, B., Saadé, N. E., Land, S. C. (2001). Thiol Regulation of Pro-Inflammatory Cytokines Reveals a Novel Immunopharmacological Potential of Glutathione in the Alveolar Epithelium. J. Pharmacol. Exp. Ther. 296: 996-1005 [Abstract] [Full Text]  
• You, M., Flick, L. M., Yu, D., Feng, G.-S. (2001). Modulation of the Nuclear Factor {kappa}b Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor. JEM 193: 101-110 [Abstract] [Full Text]  
• Swantek, J. L., Tsen, M. F., Cobb, M. H., Thomas, J. A. (2000). IL-1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin. J. Immunol. 164: 4301-4306 [Abstract] [Full Text]  
• Bocker, U., Schottelius, A., Watson, J. M., Holt, L., Licato, L. L., Brenner, D. A., Sartor, R. B., Jobin, C. (2000). Cellular Differentiation Causes a Selective Down-regulation of Interleukin (IL)-1beta -mediated NF-kappa B Activation and IL-8 Gene Expression in Intestinal Epithelial Cells. J. Biol. Chem. 275: 12207-12213 [Abstract] [Full Text]  
• Palsson, E. M., Popoff, M., Thelestam, M., O'Neill, L. A. J. (2000). Divergent Roles for Ras and Rap in the Activation of p38 Mitogen-activated Protein Kinase by Interleukin-1. J. Biol. Chem. 275: 7818-7825 [Abstract] [Full Text]  
• Thomas, J. A., Allen, J. L., Tsen, M., Dubnicoff, T., Danao, J., Liao, X. C., Cao, Z., Wasserman, S. A. (1999). Impaired Cytokine Signaling in Mice Lacking the IL-1 Receptor-Associated Kinase. J. Immunol. 163: 978-984 [Abstract] [Full Text]  
• Wesche, H., Gao, X., Li, X., Kirschning, C. J., Stark, G. R., Cao, Z. (1999). IRAK-M Is a Novel Member of the Pelle/Interleukin-1 Receptor-associated Kinase (IRAK) Family. J. Biol. Chem. 274: 19403-19410 [Abstract] [Full Text]  
• Vig, E., Green, M., Liu, Y., Donner, D. B., Mukaida, N., Goebl, M. G., Harrington, M. A. (1999). Modulation of Tumor Necrosis Factor and Interleukin-1-dependent NF-kappa B Activity by mPLK/IRAK. J. Biol. Chem. 274: 13077-13084 [Abstract] [Full Text]  
• Kanakaraj, P., Ngo, K., Wu, Y., Angulo, A., Ghazal, P., Harris, C. A., Siekierka, J. J., Peterson, P. A., Fung-Leung, W.-P. (1999). Defective Interleukin (IL)-18-mediated Natural Killer and T Helper Cell Type 1 Responses in IL-1 Receptor-associated Kinase (IRAK)-deficient Mice. JEM 189: 1129-1138 [Abstract] [Full Text]  
• Bonizzi, G., Piette, J., Schoonbroodt, S., Greimers, R., Havard, L., Merville, M.-P., Bours, V. (1999). Reactive Oxygen Intermediate-Dependent NF-kappa B Activation by Interleukin-1beta Requires 5-Lipoxygenase or NADPH Oxidase Activity. Mol. Cell. Biol. 19: 1950-1960 [Abstract] [Full Text]  
• CAO, Z., TANAKA, M., REGNIER, C., ROTHE, M., YAMIT-HEZI, A., WORONICZ, J.D., FUENTES, M.E., DURNIN, M.H., DALRYMPLE, S.A., GOEDDEL, D.V. (1999). NF-{kappa}B Activation by Tumor Necrosis Factor and Interleukin-1. Cold Spring Harb Symp Quant Biol 64: 473-484 [Abstract]  
• MacGillivray, M. K., Cruz, T. F., McCulloch, C. A. G. (2000). The Recruitment of the Interleukin-1 (IL-1) Receptor-associated Kinase (IRAK) into Focal Adhesion Complexes Is Required for IL-1beta -induced ERK Activation. J. Biol. Chem. 275: 23509-23515 [Abstract] [Full Text]  
• Born, T. L., Smith, D. E., Garka, K. E., Renshaw, B. R., Bertles, J. S., Sims, J. E. (2000). Identification and Characterization of Two Members of a Novel Class of the Interleukin-1 Receptor (IL-1R) Family. DELINEATION OF A NEW CLASS OF IL-1R-RELATED PROTEINS BASED ON SIGNALING. J. Biol. Chem. 275: 29946-29954 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS