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¹ Sir William Dunn School of Pathology, Oxford OX1 3RE, United Kingdom
² Department of Surgery, James H. Quillen College of Medicine, Johnson City, TN 37614

Address correspondence to Gordon D. Brown, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, United Kingdom. Phone: 44-1865-27-5522; Fax: 44-1865-27-5515; E-mail: gbrown{at}molbiol.ox.ac.uk

The ability of fungal-derived ß-glucan particles to induce leukocyte activation and the production of inflammatory mediators, such as tumor necrosis factor (TNF)-, is a well characterized phenomenon. Although efforts have been made to understand how these carbohydrate polymers exert their immunomodulatory effects, the receptors involved in generating these responses are unknown. Here we show that Dectin-1 mediates the production of TNF- in response to zymosan and live fungal pathogens, an activity that occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dectin-1 as well as Toll-like receptor (TLR)-2 and Myd88. This is the first demonstration that the inflammatory response to pathogens requires recognition by a specific receptor in addition to the TLRs. Furthermore, these studies implicate Dectin-1 in the production of TNF- in response to fungi, a critical step required for the successful control of these pathogens.

Key Words: ß-glucan receptor • macrophages • inflammation • tumor necrosis factor • Candida

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• Kropf, P., Freudenberg, M. A., Modolell, M., Price, H. P., Herath, S., Antoniazi, S., Galanos, C., Smith, D. F., Muller, I. (2004). Toll-Like Receptor 4 Contributes to Efficient Control of Infection with the Protozoan Parasite Leishmania major. Infect. Immun. 72: 1920-1928 [Abstract] [Full Text]  
• Fraser, I. P., Stuart, L., Ezekowitz, R. A. B. (2004). TLR-independent pattern recognition receptors and anti-inflammatory mechanisms. Innate Immunity 10: 120-124 [Abstract]  
• Diniz, S. N., Nomizo, R., Cisalpino, P. S., Teixeira, M. M., Brown, G. D., Mantovani, A., Gordon, S., Reis, L. F. L., Dias, A. A. M. (2004). PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages. J. Leukoc. Biol. 75: 649-656 [Abstract] [Full Text]  
• Netea, M. G., Sutmuller, R., Hermann, C., Van der Graaf, C. A. A., Van der Meer, J. W. M., van Krieken, J. H., Hartung, T., Adema, G., Kullberg, B. J. (2004). Toll-Like Receptor 2 Suppresses Immunity against Candida albicans through Induction of IL-10 and Regulatory T Cells. J. Immunol. 172: 3712-3718 [Abstract] [Full Text]  
• Lee, H.-K., Dunzendorfer, S., Tobias, P. S. (2004). Cytoplasmic Domain-mediated Dimerizations of Toll-like Receptor 4 Observed by {beta}-Lactamase Enzyme Fragment Complementation. J. Biol. Chem. 279: 10564-10574 [Abstract] [Full Text]  
• Bellocchio, S., Montagnoli, C., Bozza, S., Gaziano, R., Rossi, G., Mambula, S. S., Vecchi, A., Mantovani, A., Levitz, S. M., Romani, L. (2004). The Contribution of the Toll-Like/IL-1 Receptor Superfamily to Innate and Adaptive Immunity to Fungal Pathogens In Vivo. J. Immunol. 172: 3059-3069 [Abstract] [Full Text]  
• Li, C., Ha, T., Kelley, J., Gao, X., Qiu, Y., Kao, R. L, Browder, W., Williams, D. L (2004). Modulating Toll-like receptor mediated signaling by (1->3)-{beta}-D-glucan rapidly induces cardioprotection. Cardiovasc Res 61: 538-547 [Abstract] [Full Text]  
• Taylor, P. R., Brown, G. D., Herre, J., Williams, D. L., Willment, J. A., Gordon, S. (2004). The Role of SIGNR1 and the {beta}-Glucan Receptor (Dectin-1) in the Nonopsonic Recognition of Yeast by Specific Macrophages. J. Immunol. 172: 1157-1162 [Abstract] [Full Text]  
• Romani, L., Montagnoli, C., Bozza, S., Perruccio, K., Spreca, A., Allavena, P., Verbeek, S., Calderone, R. A., Bistoni, F., Puccetti, P. (2004). The exploitation of distinct recognition receptors in dendritic cells determines the full range of host immune relationships with Candida albicans. Int Immunol 16: 149-161 [Abstract] [Full Text]  
• Romagnoli, G., Nisini, R., Chiani, P., Mariotti, S., Teloni, R., Cassone, A., Torosantucci, A. (2004). The interaction of human dendritic cells with yeast and germ-tube forms of Candida albicans leads to efficient fungal processing, dendritic cell maturation, and acquisition of a Th1 response-promoting function. J. Leukoc. Biol. 75: 117-126 [Abstract] [Full Text]  
• Fernandez, N., Renedo, M., Alonso, S., Crespo, M. S. (2003). Release of Arachidonic Acid by Stimulation of Opsonic Receptors in Human Monocytes: THE Fc{gamma}R AND THE COMPLEMENT RECEPTOR 3 PATHWAYS. J. Biol. Chem. 278: 52179-52187 [Abstract] [Full Text]  
• Steele, C., Marrero, L., Swain, S., Harmsen, A. G., Zheng, M., Brown, G. D., Gordon, S., Shellito, J. E., Kolls, J. K. (2003). Alveolar Macrophage-mediated Killing of Pneumocystis carinii f. sp. muris Involves Molecular Recognition by the Dectin-1 {beta}-Glucan Receptor. JEM 198: 1677-1688 [Abstract] [Full Text]  
• Willment, J. A., Lin, H.-H., Reid, D. M., Taylor, P. R., Williams, D. L., Wong, S. Y. C., Gordon, S., Brown, G. D. (2003). Dectin-1 Expression and Function Are Enhanced on Alternatively Activated and GM-CSF-Treated Macrophages and Are Negatively Regulated by IL-10, Dexamethasone, and Lipopolysaccharide. J. Immunol. 171: 4569-4573 [Abstract] [Full Text]  
• Sabroe, I., Read, R. C., Whyte, M. K. B., Dockrell, D. H., Vogel, S. N., Dower, S. K. (2003). Toll-Like Receptors in Health and Disease: Complex Questions Remain. J. Immunol. 171: 1630-1635 [Full Text]  

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