Brief Definitive Report

Immune Cell Activation by Bacterial CpG-DNA through Myeloid Differentiation Marker 88 and Tumor Necrosis Factor Receptor–Associated Factor (TRAF)6

Correspondence to: Hans Häcker, Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Trogerstr. 9, D-81675 Munich, Germany. Tel:49-89-4140-4184 Fax:49-89-4140-4868 E-mail:hans.haecker{at}lrz.tum.de.

Transition of immature antigen presenting cells (APCs) to the state of professional APCs is essential for initiation of cell-mediated immune responses to pathogens. Signal transduction via molecules of the Toll-like receptor (TLR)/interleukin 1 receptor (IL-1R) pathway is critical for activation of APCs either by pathogen-derived pattern ligands like lipopolysaccharides (LPS) or by CD40 ligation through T helper cells. The capacity of bacterial DNA (CpG-DNA) to induce APCs to differentiate into professional APCs represents an interesting discovery. However, the signaling pathways involved are poorly understood. Here we show that CpG-DNA activates the TLR/IL-1R signaling pathway via the molecules myeloid differentiation marker 88 (MyD88) and tumor necrosis factor receptor–associated factor 6 (TRAF6), leading to activation of kinases of the IB kinase complex and the c-jun NH₂-terminal kinases. Moreover, cells of TLR2- and TLR4-deficient mice are activated by CpG-DNA, whereas cells of MyD88-deficient mice do not respond. The data suggest that CpG-DNA initiates signaling via the TLR/IL-1R pathway in APCs in a manner similar to LPS and to T helper cell–mediated CD40 ligation. Activation of the TLR/IL-1R signaling pathway by foreign bacterial DNA may be one way to initiate innate defense mechanisms against infectious pathogens in vivo.

Key Words: Toll, signal transduction, CpG-DNA, interleukin 12, mice, knockout

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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]  
• Gao, J. J., Xue, Q., Papasian, C. J., Morrison, D. C. (2001). Bacterial DNA and Lipopolysaccharide Induce Synergistic Production of TNF-{{alpha}} Through a Post-Transcriptional Mechanism. J. Immunol. 166: 6855-6860 [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]  
• Kadowaki, N., Antonenko, S., Liu, Y.-J. (2001). Distinct CpG DNA and Polyinosinic-Polycytidylic Acid Double-Stranded RNA, Respectively, Stimulate CD11c- Type 2 Dendritic Cell Precursors and CD11c+ Dendritic Cells to Produce Type I IFN. J. Immunol. 166: 2291-2295 [Abstract] [Full Text]  
• Akira, S., Hoshino, K., Kaisho, T. (2000). The role of Toll-like receptors and MyD88 in innate immune responses. Innate Immunity 6: 383-387 [Abstract]  
• Vabulas, R. M., Ahmad-Nejad, P., da Costa, C., Miethke, T., Kirschning, C. J., Hacker, H., Wagner, H. (2001). Endocytosed HSP60s Use Toll-like Receptor 2 (TLR2) and TLR4 to Activate the Toll/Interleukin-1 Receptor Signaling Pathway in Innate Immune Cells. J. Biol. Chem. 276: 31332-31339 [Abstract] [Full Text]  
• Bauer, S., Kirschning, C. J., Hacker, H., Redecke, V., Hausmann, S., Akira, S., Wagner, H., Lipford, G. B. (2001). Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl. Acad. Sci. USA 98: 9237-9242 [Abstract] [Full Text]  

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