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*
Interdisciplinary Graduate Program in Immunology and Department of Internal Medicine, University of Iowa College of Medicine, and
University of Iowa College of Pharmacy, Iowa City, IA 52242; and
Department of Veteran Affairs Medical Center, Iowa City, IA 52246
B cells and monocytes endocytose DNA into an acidified
intracellular compartment. If this DNA contains unmethylated CpG
dinucleotides in particular base contexts (CpG motifs), these
leukocytes are rapidly activated. We now show that both B cell and
monocyte-like cell line responses to DNA containing CpG motifs (CpG
DNA) are sensitive to endosomal acidification inhibitors; they are
completely blocked by bafilomycin A, chloroquine, and monensin. The
specificity of these inhibitors is demonstrated by their failure to
prevent responses to LPS, PMA, or ligation of CD40 or IgM.
Acidification of endosomal CpG DNA is coupled to the rapid generation
of intracellular reactive oxygen species. The CpG DNA-induced reactive
oxygen species burst is linked to the degradation of I
B and the
activation of NFB, which induces leukocyte gene transcription and
cytokine secretion. These studies demonstrate a novel pathway of
leukocyte activation triggered by CpG motifs.
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S. K. Datta, V. Redecke, K. R. Prilliman, K. Takabayashi, M. Corr, T. Tallant, J. DiDonato, R. Dziarski, S. Akira, S. P. Schoenberger, et al. A Subset of Toll-Like Receptor Ligands Induces Cross-presentation by Bone Marrow-Derived Dendritic Cells J. Immunol., April 15, 2003; 170(8): 4102 - 4110. [Abstract] [Full Text] [PDF]
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P. Riedl, D. Stober, C. Oehninger, K. Melber, J. Reimann, and R. Schirmbeck Priming Th1 Immunity to Viral Core Particles Is Facilitated by Trace Amounts of RNA Bound to Its Arginine-Rich Domain J. Immunol., May 15, 2002; 168(10): 4951 - 4959. [Abstract] [Full Text] [PDF]
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A.-K. Yi, J.-G. Yoon, S.-J. Yeo, S.-C. Hong, B. K. English, and A. M. Krieg Role of Mitogen-Activated Protein Kinases in CpG DNA-Mediated IL-10 and IL-12 Production: Central Role of Extracellular Signal-Regulated Kinase in the Negative Feedback Loop of the CpG DNA-Mediated Th1 Response J. Immunol., May 1, 2002; 168(9): 4711 - 4720. [Abstract] [Full Text] [PDF]
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T.-H. Chuang, J. Lee, L. Kline, J. C. Mathison, and R. J. Ulevitch Toll-like receptor 9 mediates CpG-DNA signaling J. Leukoc. Biol., March 1, 2002; 71(3): 538 - 544. [Abstract] [Full Text] [PDF]
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A.-K. Yi, J.-G. Yoon, S.-C. Hong, T. W. Redford, and A. M. Krieg Lipopolysaccharide and CpG DNA synergize for tumor necrosis factor-{alpha} production through activation of NF-{kappa}B Int. Immunol., November 1, 2001; 13(11): 1391 - 1404. [Abstract] [Full Text] [PDF]
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F. Takeshita, C. A. Leifer, I. Gursel, K. J. Ishii, S. Takeshita, M. Gursel, and D. M. Klinman Cutting Edge: Role of Toll-Like Receptor 9 in CpG DNA-Induced Activation of Human Cells J. Immunol., October 1, 2001; 167(7): 3555 - 3558. [Abstract] [Full Text] [PDF]
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J. R. Bosarge, J. M. Watt, D. O. McDaniel, E. Swiatlo, and L. S. McDaniel Genetic Immunization with the Region Encoding the {alpha}-Helical Domain of PspA Elicits Protective Immunity against Streptococcus pneumoniae Infect. Immun., September 1, 2001; 69(9): 5456 - 5463. [Abstract] [Full Text] [PDF]
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K. H. Baek, S. J. Ha, and Y. C. Sung A Novel Function of Phosphorothioate Oligodeoxynucleotides as Chemoattractants for Primary Macrophages J. Immunol., September 1, 2001; 167(5): 2847 - 2854. [Abstract] [Full Text] [PDF]
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B. E. Britigan, T. S. Lewis, M. Waldschmidt, M. L. McCormick, and A. M. Krieg Lactoferrin Binds CpG-Containing Oligonucleotides and Inhibits Their Immunostimulatory Effects on Human B Cells J. Immunol., September 1, 2001; 167(5): 2921 - 2928. [Abstract] [Full Text] [PDF]
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M Miyata, O Ito, H Kobayashi, T Sasajima, H Ohira, S Suzuki, and R Kasukawa CpG-DNA derived from sera in systemic lupus erythematosus enhances ICAM-1 expression on endothelial cells Ann Rheum Dis, July 1, 2001; 60(7): 685 - 689. [Abstract] [Full Text] [PDF]
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 T. Suzuki, M. Yamaya, K. Sekizawa, M. Hosoda, N. Yamada, S. Ishizuka, K. Nakayama, M. Yanai, Y. Numazaki, and H. Sasaki Bafilomycin A1 inhibits rhinovirus infection in human airway epithelium: effects on endosome and ICAM-1 Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1115 - L1127. [Abstract] [Full Text] [PDF]
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J. J. Gao, Q. Xue, C. J. Papasian, and D. C. Morrison Bacterial DNA and Lipopolysaccharide Induce Synergistic Production of TNF-{{alpha}} Through a Post-Transcriptional Mechanism J. Immunol., June 1, 2001; 166(11): 6855 - 6860. [Abstract] [Full Text] [PDF]
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T. D. Crabtree, L. Jin, D. P. Raymond, S. J. Pelletier, C. W. Houlgrave, T. G. Gleason, T. L. Pruett, and R. G. Sawyer Preexposure of Murine Macrophages to CpG Oligonucleotide Results in a Biphasic Tumor Necrosis Factor Alpha Response to Subsequent Lipopolysaccharide Challenge Infect. Immun., April 1, 2001; 69(4): 2123 - 2129. [Abstract] [Full Text] [PDF]
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S. W. Lee, M. K. Song, K. H. Baek, Y. Park, J. K. Kim, C. H. Lee, H.-K. Cheong, C. Cheong, and Y. C. Sung Effects of a Hexameric Deoxyriboguanosine Run Conjugation into CpG Oligodeoxynucleotides on Their Immunostimulatory Potentials J. Immunol., October 1, 2000; 165(7): 3631 - 3639. [Abstract] [Full Text] [PDF]
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H. Hacker, R. M. Vabulas, O. Takeuchi, K. Hoshino, S. Akira, and H. Wagner Immune Cell Activation by Bacterial Cpg-DNA through Myeloid Differentiation Marker 88 and Tumor Necrosis Factor Receptor-Associated Factor (Traf)6 J. Exp. Med., August 21, 2000; 192(4): 595 - 600. [Abstract] [Full Text] [PDF]
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H. Liang, C. F. Reich, D. S. Pisetsky, and P. E. Lipsky The Role of Cell Surface Receptors in the Activation of Human B Cells by Phosphorothioate Oligonucleotides J. Immunol., August 1, 2000; 165(3): 1438 - 1445. [Abstract] [Full Text] [PDF]
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G. Hartmann, R. D. Weeratna, Z. K. Ballas, P. Payette, S. Blackwell, I. Suparto, W. L. Rasmussen, M. Waldschmidt, D. Sajuthi, R. H. Purcell, et al. Delineation of a CpG Phosphorothioate Oligodeoxynucleotide for Activating Primate Immune Responses In Vitro and In Vivo J. Immunol., February 1, 2000; 164(3): 1617 - 1624. [Abstract] [Full Text] [PDF]
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G. Hartmann and A. M. Krieg Mechanism and Function of a Newly Identified CpG DNA Motif in Human Primary B Cells J. Immunol., January 15, 2000; 164(2): 944 - 953. [Abstract] [Full Text] [PDF]
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D. P. Sester, S. J. Beasley, M. J. Sweet, L. F. Fowles, S. L. Cronau, K. J. Stacey, and D. A. Hume Bacterial/CpG DNA Down-Modulates Colony Stimulating Factor-1 Receptor Surface Expression on Murine Bone Marrow-Derived Macrophages with Concomitant Growth Arrest and Factor-Independent Survival J. Immunol., December 15, 1999; 163(12): 6541 - 6550. [Abstract] [Full Text] [PDF]
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L. Manzel, L. Strekowski, F. M. D. Ismail, J. C. Smith, and D. E. Macfarlane Antagonism of Immunostimulatory CpG-Oligodeoxynucleotides by 4-Aminoquinolines and Other Weak Bases: Mechanistic Studies J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1337 - 1347. [Abstract] [Full Text]
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A.-K. Yi, D. W. Peckham, R. F. Ashman, and A. M. Krieg CpG DNA rescues B cells from apoptosis by activating NF{kappa}B and preventing mitochondrial membrane potential disruption via a chloroquine-sensitive pathway Int. Immunol., December 1, 1999; 11(12): 2015 - 2024. [Abstract] [Full Text] [PDF]
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J. J. Gao, E. G. Zuvanich, Q. Xue, D. L. Horn, R. Silverstein, and D. C. Morrison Cutting Edge: Bacterial DNA and LPS Act in Synergy in Inducing Nitric Oxide Production in RAW 264.7 Macrophages J. Immunol., October 15, 1999; 163(8): 4095 - 4099. [Abstract] [Full Text] [PDF]
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J. S. Cowdery, N. J. Boerth, L. A. Norian, P. S. Myung, and G. A. Koretzky Differential Regulation of the IL-12 p40 Promoter and of p40 Secretion by CpG DNA and Lipopolysaccharide J. Immunol., June 1, 1999; 162(11): 6770 - 6775. [Abstract] [Full Text] [PDF]
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 A. Oxenius, M. M. A. Martinic, H. Hengartner, and P. Klenerman CpG-Containing Oligonucleotides Are Efficient Adjuvants for Induction of Protective Antiviral Immune Responses with T-Cell Peptide Vaccines J. Virol., May 1, 1999; 73(5): 4120 - 4126. [Abstract] [Full Text]
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D. Broide, J. Schwarze, H. Tighe, T. Gifford, M.-D. Nguyen, S. Malek, J. Van Uden, E. Martin-Orozco, E. W. Gelfand, and E. Raz Immunostimulatory DNA Sequences Inhibit IL-5, Eosinophilic Inflammation, and Airway Hyperresponsiveness in Mice J. Immunol., December 15, 1998; 161(12): 7054 - 7062. [Abstract] [Full Text] [PDF]
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A.-K. Yi and A. M. Krieg Cutting Edge: Rapid Induction of Mitogen-Activated Protein Kinases by Immune Stimulatory CpG DNA J. Immunol., November 1, 1998; 161(9): 4493 - 4497. [Abstract] [Full Text] [PDF]
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T. W. Redford, A.-K. Yi, C. T. Ward, and A. M. Krieg Cyclosporin A Enhances IL-12 Production by CpG Motifs in Bacterial DNA and Synthetic Oligodeoxynucleotides J. Immunol., October 15, 1998; 161(8): 3930 - 3935. [Abstract] [Full Text] [PDF]
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 A. M. Krieg, T. Wu, R. Weeratna, S. M. Efler, L. Love-Homan, L. Yang, A.-K. Yi, D. Short, and H. L. Davis Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs PNAS, October 13, 1998; 95(21): 12631 - 12636. [Abstract] [Full Text] [PDF]
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