The Human Toll Signaling Pathway: Divergence of Nuclear Factor {kappa}B and JNK/SAPK Activation Upstream of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6)

doi:10.1084/jem.187.12.2097

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© The Rockefeller University Press, 0022-1007/1998/6/2097/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 12, June 15, 1998 2097-2101

Brief Definitive Reports

The Human Toll Signaling Pathway: Divergence of Nuclear Factor ${kappa}$ B and JNK/SAPK Activation Upstream of Tumor Necrosis Factor Receptor–associated Factor 6 (TRAF6)

Marta Muzio^*, Gioacchino Natoli, Simona Saccani^*, Massimo Levrero, and Alberto Mantovani^*^,

From the ^* Department of Immunology and Cell Biology, Mario Negri Institute, I-20157 Milan, Italy; Istituto di I Clinica Medica, Policlinico Umberto I, I-00161 Rome, Italy; and Department of Biotechnology, University of Brescia, 25123 Brescia, Italy

The human homologue of Drosophila Toll (hToll) is a recentlycloned receptor of the interleukin 1 receptor (IL-1R) superfamily,and has been implicated in the activation of adaptive immunity.Signaling by hToll is shown to occur through sequential recruitmentof the adapter molecule MyD88 and the IL-1R–associatedkinase. Tumor necrosis factor receptor–activated factor6 (TRAF6) and the nuclear factor ${kappa}$ B (NF- ${kappa}$ B)–inducing kinase(NIK) are both involved in subsequent steps of NF- ${kappa}$ B activation.Conversely, a dominant negative version of TRAF6 failed toblock hToll-induced activation of stress-activated protein kinase/c-JunNH₂-terminal kinases, thus suggesting an early divergence ofthe two pathways.

Key Words: Toll • interleukin 1 receptor • nuclear factor ${kappa}$ B • c-Jun NH₂-terminal kinase/ stress-activated protein kinase

Address correspondence to Marta Muzio, Dept. Immunology andCell Biology, Mario Negri Institute, via Eritrea 62, I-20157,Milano, Italy. Phone: 39-2-39014532; Fax: 39-2-3546277; E-mail:muziom{at}irfmn.mnegri.it

M. Muzio is supported by Federazione Italiana Ricerca sul Cancro.This work was supported by European Community Special ProjectBiotechnology, Consiglio Nazionale Ricerche, and AssociazioneItaliana Ricerca sul Cancro.

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Dalpke, A. H., Opper, S., Zimmermann, S., Heeg, K. (2001). Suppressors of Cytokine Signaling (SOCS)-1 and SOCS-3 Are Induced by CpG-DNA and Modulate Cytokine Responses in APCs. J. Immunol. 166: 7082-7089 [Abstract] [Full Text]
Alexander, C., Rietschel, E. Th. (2001). Invited review: Bacterial lipopolysaccharides and innate immunity. Innate Immunity 7: 167-202 [Abstract]
Jones, B. W., Means, T. K., Heldwein, K. A., Keen, M. A., Hill, P. J., Belisle, J. T., Fenton, M. J. (2001). Different Toll-like receptor agonists induce distinct macrophage responses. J. Leukoc. Biol. 69: 1036-1044 [Abstract] [Full Text]
Liu, Y., Wang, Y., Yamakuchi, M., Isowaki, S., Nagata, E., Kanmura, Y., Kitajima, I., Maruyama, I. (2001). Upregulation of Toll-Like Receptor 2 Gene Expression in Macrophage Response to Peptidoglycan and High Concentration of Lipopolysaccharide Is Involved in NF-{kappa}B Activation. Infect. Immun. 69: 2788-2796 [Abstract] [Full Text]
Kaisho, T., Takeuchi, O., Kawai, T., Hoshino, K., Akira, S. (2001). Endotoxin-Induced Maturation of MyD88-Deficient Dendritic Cells. J. Immunol. 166: 5688-5694 [Abstract] [Full Text]
Bauer, M., Redecke, V., Ellwart, J. W., Scherer, B., Kremer, J.-P., Wagner, H., Lipford, G. B. (2001). Bacterial CpG-DNA Triggers Activation and Maturation of Human CD11c-, CD123+ Dendritic Cells. J. Immunol. 166: 5000-5007 [Abstract] [Full Text]
Shoham, S., Huang, C., Chen, J.-M., Golenbock, D. T., Levitz, S. M. (2001). Toll-Like Receptor 4 Mediates Intracellular Signaling Without TNF-{{alpha}} Release in Response to Cryptococcus neoformans Polysaccharide Capsule. J. Immunol. 166: 4620-4626 [Abstract] [Full Text]
Haudek, S. B., Spencer, E., Bryant, D. D., White, D. J., Maass, D., Horton, J. W., Chen, Z. J., Giroir, B. P. (2001). Overexpression of cardiac I-{kappa}B{alpha} prevents endotoxin-induced myocardial dysfunction. Am. J. Physiol. Heart Circ. Physiol. 280: H962-H968 [Abstract] [Full Text]
Equils, O., Faure, E., Thomas, L., Bulut, Y., Trushin, S., Arditi, M. (2001). Bacterial Lipopolysaccharide Activates HIV Long Terminal Repeat Through Toll-Like Receptor 4. J. Immunol. 166: 2342-2347 [Abstract] [Full Text]
Schmidt, A., Caron, E., Hall, A. (2001). Lipopolysaccharide-Induced Activation of {beta}2-Integrin Function in Macrophages Requires Irak Kinase Activity, p38 Mitogen- Activated Protein Kinase, and the Rap1 GTPase. Mol. Cell. Biol. 21: 438-448 [Abstract] [Full Text]
Krishna Rao, K. M. (2001). MAP kinase activation in macrophages. J. Leukoc. Biol. 69: 3-10 [Abstract] [Full Text]
Visintin, A., Mazzoni, A., Spitzer, J. H., Wyllie, D. H., Dower, S. K., Segal, D. M. (2001). Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells. J. Immunol. 166: 249-255 [Abstract] [Full Text]
Sato, S., Nomura, F., Kawai, T., Takeuchi, O., Muhlradt, P. F., Takeda, K., Akira, S. (2000). Synergy and Cross-Tolerance Between Toll-Like Receptor (TLR) 2- and TLR4-Mediated Signaling Pathways. J. Immunol. 165: 7096-7101 [Abstract] [Full Text]
Wyllie, D. H., Kiss-Toth, E., Visintin, A., Smith, S. C., Boussouf, S., Segal, D. M., Duff, G. W., Dower, S. K. (2000). Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses. J. Immunol. 165: 7125-7132 [Abstract] [Full Text]
Brunner, C., Seiderer, J., Schlamp, A., Bidlingmaier, M., Eigler, A., Haimerl, W., Lehr, H.-A., Krieg, A. M., Hartmann, G., Endres, S. (2000). Enhanced Dendritic Cell Maturation by TNF-{alpha} or Cytidine-Phosphate-Guanosine DNA Drives T Cell Activation In Vitro and Therapeutic Anti-Tumor Immune Responses In Vivo. J. Immunol. 165: 6278-6286 [Abstract] [Full Text]
Takeuchi, O., Hoshino, K., Akira, S. (2000). Cutting Edge: TLR2-Deficient and MyD88-Deficient Mice Are Highly Susceptible to Staphylococcus aureus Infection. J. Immunol. 165: 5392-5396 [Abstract] [Full Text]