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The Journal of Immunology, Vol 157, Issue 12 5394-5402, Copyright © 1996 by American Association of Immunologists
ARTICLES |
AK Yi, DM Klinman, TL Martin, S Matson and AM Krieg
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
Unmethylated CpG dinucleotides (CpG motif) in bacterial DNA or synthetic oligodeoxynucleotides (CpG DNA) rapidly activate murine B cells to secrete IL-6 and IgM, as well as to proliferate. Within 30 min after CpG DNA stimulation in vivo, IL-6 mRNA levels were increased in liver, spleen, and thymus cells. Serum IL-6 protein was markedly increased within 1 h of stimulation. Treatment of a B cell line with CpG DNA led to an increase in the transcriptional activity of the IL-6 promoter. This CpG DNA-induced IL-6 production was not mediated via either a protein kinase C (PKC)-, protein kinase A (PKA)-, or nitric oxide (NO.)-dependent pathway but was inhibited by an antioxidant. In addition, the level of intracellular reactive oxygen species was increased within 20 min after CpG DNA, but not control non-CpG DNA, treatment. These results suggest that CpG DNA-induced IL-6 production is mediated through a reactive oxygen intermediate-dependent pathway. CpG DNA-mediated IL-6 production was enhanced by simultaneous signals delivered through the Ag receptor. The addition of neutralizing Abs against IL-6 to B cell cultures along with CpG oligodeoxynucleotides essentially abolished the CpG DNA-induced increased IgM secretion but had no significant effect on the B cell proliferation induced by the CpG motif. Our results suggest that the induction of IL-6 expression in response to CpG motifs in bacterial DNA may be an important immune defense mechanism that facilitates a rapid response to microbial infection.
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D. A. Schwartz, C. L. Wohlford-Lenane, T. J. Quinn, and A. M. Krieg Bacterial DNA or Oligonucleotides Containing Unmethylated CpG Motifs Can Minimize Lipopolysaccharide-Induced Inflammation in the Lower Respiratory Tract Through an IL-12-Dependent Pathway J. Immunol., July 1, 1999; 163(1): 224 - 231. [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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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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P. Brandler, K. U. Saikh, D. Heath, A. Friedlander, and R. G. Ulrich Weak Anamnestic Responses of Inbred Mice to Yersinia F1 Genetic Vaccine Are Overcome by Boosting with F1 Polypeptide While Outbred Mice Remain Nonresponsive J. Immunol., October 15, 1998; 161(8): 4195 - 4200. [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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T. Jakob, P. S. Walker, A. M. Krieg, M. C. Udey, and J. C. Vogel Activation of Cutaneous Dendritic Cells by CpG-Containing Oligodeoxynucleotides: A Role for Dendritic Cells in the Augmentation of Th1 Responses by Immunostimulatory DNA J. Immunol., September 15, 1998; 161(6): 3042 - 3049. [Abstract] [Full Text] [PDF]
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A. M. Krieg, L. Love-Homan, A.-K. Yi, and J. T. Harty CpG DNA Induces Sustained IL-12 Expression In Vivo and Resistance to Listeria monocytogenes Challenge J. Immunol., September 1, 1998; 161(5): 2428 - 2434. [Abstract] [Full Text] [PDF]
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A.-K. Yi, M. Chang, D. W. Peckham, A. M. Krieg, and R. F. Ashman CpG Oligodeoxyribonucleotides Rescue Mature Spleen B Cells from Spontaneous Apoptosis and Promote Cell Cycle Entry J. Immunol., June 15, 1998; 160(12): 5898 - 5906. [Abstract] [Full Text] [PDF]
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A.-K. Yi, R. Tuetken, T. Redford, M. Waldschmidt, J. Kirsch, and A. M. Krieg CpG Motifs in Bacterial DNA Activate Leukocytes Through the pH-Dependent Generation of Reactive Oxygen Species J. Immunol., May 15, 1998; 160(10): 4755 - 4761. [Abstract] [Full Text] [PDF]
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S. Zimmermann, O. Egeter, S. Hausmann, G. B. Lipford, M. Rocken, H. Wagner, and K. Heeg Cutting Edge: CpG Oligodeoxynucleotides Trigger Protective and Curative Th1 Responses in Lethal Murine Leishmaniasis J. Immunol., April 15, 1998; 160(8): 3627 - 3630. [Abstract] [Full Text] [PDF]
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A.-K. Yi and A. M. Krieg CpG DNA Rescue from Anti-IgM-Induced WEHI-231 B Lymphoma Apoptosis via Modulation of I{kappa}B{alpha} and I{kappa}B{beta} and Sustained Activation of Nuclear Factor-{kappa}B/c-Rel J. Immunol., February 1, 1998; 160(3): 1240 - 1245. [Abstract] [Full Text] [PDF]
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H. L. Davis, R. Weeranta, T. J. Waldschmidt, L. Tygrett, J. Schorr, and A. M. Krieg CpG DNA Is a Potent Enhancer of Specific Immunity in Mice Immunized with Recombinant Hepatitis B Surface Antigen J. Immunol., January 15, 1998; 160(2): 870 - 876. [Abstract] [Full Text] [PDF]
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G. J. Weiner, H.-M. Liu, J. E. Wooldridge, C. E. Dahle, and A. M. Krieg Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization PNAS, September 30, 1997; 94(20): 10833 - 10837. [Abstract] [Full Text] [PDF]
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J. E. Wooldridge, Z. Ballas, A. M. Krieg, and G. J. Weiner Immunostimulatory Oligodeoxynucleotides Containing CpG Motifs Enhance the Efficacy of Monoclonal Antibody Therapy of Lymphoma Blood, April 15, 1997; 89(8): 2994 - 2998. [Abstract] [Full Text] [PDF]
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