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Science 28 November 1997:
Vol. 278. no. 5343, pp. 1612 - 1615
DOI: 10.1126/science.278.5343.1612
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Reports

IRAK (Pelle) Family Member IRAK-2 and MyD88 as Proximal Mediators of IL-1 Signaling

Marta Muzio, * Jian Ni, Ping Feng, Vishva M. Dixit dagger

The interleukin-1 receptor (IL-1R) signaling pathway leads to nuclear factor kappa B (NF-kappa B) activation in mammals and is similar to the Toll pathway in Drosophila: the IL-1R-associated kinase (IRAK) is homologous to Pelle. Two additional proximal mediators were identified that are required for IL-1R-induced NF-kappa B activation: IRAK-2, a Pelle family member, and MyD88, a death domain-containing adapter molecule. Both associate with the IL-1R signaling complex. Dominant negative forms of either attenuate IL-1R-mediated NF-kappa B activation. Therefore, IRAK-2 and MyD88 may provide additional therapeutic targets for inhibiting IL-1-induced inflammation.

M. Muzio and V. M. Dixit, University of Michigan Medical School, Department of Pathology, Ann Arbor, MI 48109, USA.
J. Ni and P. Feng, Human Genome Sciences, Rockville, MD 20850-9998, USA.
*   Present address: Mario Negri Institute, Milano, Italy.

dagger    To whom correspondence should be addressed. Present address: Genentech, South San Francisco, CA 94080, USA. E-mail: dixit{at}gene.com

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Different Domains of Pseudomonas aeruginosa Exoenzyme S Activate Distinct TLRs.
S. Epelman, D. Stack, C. Bell, E. Wong, G. G. Neely, S. Krutzik, K. Miyake, P. Kubes, L. D. Zbytnuik, L. L. Ma, et al. (2004)
J. Immunol. 173, 2031-2040
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Gene expression profiles during human CD4+ T cell differentiation.
M. S. Lee, K. Hanspers, C. S. Barker, A. P. Korn, and J. M. McCune (2004)
Int. Immunol. 16, 1109-1124
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Microbial DNA Induces a Host Defense Reaction of Human Respiratory Epithelial Cells.
J. Platz, C. Beisswenger, A. Dalpke, R. Koczulla, O. Pinkenburg, C. Vogelmeier, and R. Bals (2004)
J. Immunol. 173, 1219-1223
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The Murine Irak2 Gene Encodes Four Alternatively Spliced Isoforms, Two of Which Are Inhibitory.
M. P. Hardy and L. A. J. O'Neill (2004)
J. Biol. Chem. 279, 27699-27708
   Abstract »    Full Text »    PDF »
Rac1 and Toll-IL-1 Receptor Domain-Containing Adapter Protein Mediate Toll-Like Receptor 4 Induction of HIV-Long Terminal Repeat.
O. Equils, Z. Madak, C. Liu, K. S. Michelsen, Y. Bulut, and D. Lu (2004)
J. Immunol. 172, 7642-7646
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Lipopolysaccharide initiates a TRAF6-mediated endothelial survival signal.
F. Wong, C. Hull, R. Zhande, J. Law, and A. Karsan (2004)
Blood 103, 4520-4526
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Toll-Like Receptors in Normal and Cystic Fibrosis Airway Epithelial Cells.
A. Muir, G. Soong, S. Sokol, B. Reddy, M. I. Gomez, A. van Heeckeren, and A. Prince (2004)
Am. J. Respir. Cell Mol. Biol. 30, 777-783
   Abstract »    Full Text »    PDF »
Recognition of single-stranded RNA viruses by Toll-like receptor 7.
J. M. Lund, L. Alexopoulou, A. Sato, M. Karow, N. C. Adams, N. W. Gale, A. Iwasaki, and R. A. Flavell (2004)
PNAS 101, 5598-5603
   Abstract »    Full Text »    PDF »
Mechanisms of the TRIF-induced Interferon-stimulated Response Element and NF-{kappa}B Activation and Apoptosis Pathways.
K.-J. Han, X. Su, L.-G. Xu, L.-H. Bin, J. Zhang, and H.-B. Shu (2004)
J. Biol. Chem. 279, 15652-15661
   Abstract »    Full Text »    PDF »
Signaling Danger: Toll-Like Receptors and their Potential Roles in Kidney Disease.
H.-J. Anders, B. Banas, and D. Schlondorff (2004)
J. Am. Soc. Nephrol. 15, 854-867
   Abstract »    Full Text »    PDF »
Distinct pathways of LPS-induced NF-{kappa}B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP.
E. Andreakos, S. M. Sacre, C. Smith, A. Lundberg, S. Kiriakidis, T. Stonehouse, C. Monaco, M. Feldmann, and B. M. Foxwell (2004)
Blood 103, 2229-2237
   Abstract »    Full Text »    PDF »
Shielding the double-edged sword: negative regulation of the innate immune system.
K. S. Kobayashi and R. A. Flavell (2004)
J. Leukoc. Biol. 75, 428-433
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The Contribution of the Toll-Like/IL-1 Receptor Superfamily to Innate and Adaptive Immunity to Fungal Pathogens In Vivo.
S. Bellocchio, C. Montagnoli, S. Bozza, R. Gaziano, G. Rossi, S. S. Mambula, A. Vecchi, A. Mantovani, S. M. Levitz, and L. Romani (2004)
J. Immunol. 172, 3059-3069
   Abstract »    Full Text »    PDF »
Involvement of Toll-like Receptors 2 and 4 in Cellular Activation by High Mobility Group Box 1 Protein.
J. S. Park, D. Svetkauskaite, Q. He, J.-Y. Kim, D. Strassheim, A. Ishizaka, and E. Abraham (2004)
J. Biol. Chem. 279, 7370-7377
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Involvement of IRAK-M in Peptidoglycan-induced Tolerance in Macrophages.
K. Nakayama, S. Okugawa, S. Yanagimoto, T. Kitazawa, K. Tsukada, M. Kawada, S. Kimura, K. Hirai, Y. Takagaki, and Y. Ota (2004)
J. Biol. Chem. 279, 6629-6634
   Abstract »    Full Text »    PDF »
Sequential Autophosphorylation Steps in the Interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling.
C. Kollewe, A.-C. Mackensen, D. Neumann, J. Knop, P. Cao, S. Li, H. Wesche, and M. U. Martin (2004)
J. Biol. Chem. 279, 5227-5236
   Abstract »    Full Text »    PDF »
Response of Human Pulmonary Epithelial Cells to Lipopolysaccharide Involves Toll-like Receptor 4 (TLR4)-dependent Signaling Pathways: EVIDENCE FOR AN INTRACELLULAR COMPARTMENTALIZATION OF TLR4.
L. Guillot, S. Medjane, K. Le-Barillec, V. Balloy, C. Danel, M. Chignard, and M. Si-Tahar (2004)
J. Biol. Chem. 279, 2712-2718
   Abstract »    Full Text »    PDF »
Adjuvant-Mediated Tumor Regression and Tumor-Specific Cytotoxic Response Are Impaired in MyD88-Deficient Mice.
T. Akazawa, H. Masuda, Y. Saeki, M. Matsumoto, K. Takeda, K. Tsujimura, K. Kuzushima, T. Takahashi, I. Azuma, S. Akira, et al. (2004)
Cancer Res. 64, 757-764
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Neutrophil Gelatinase-Associated Lipocalin Is Up-Regulated in Human Epithelial Cells by IL-1{beta}, but Not by TNF-{alpha}.
J. B. Cowland, O. E. Sorensen, M. Sehested, and N. Borregaard (2003)
J. Immunol. 171, 6630-6639
   Abstract »    Full Text »    PDF »


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