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Research ArticleArticle

Antagonism of Immunostimulatory CpG-Oligodeoxynucleotides by 4-Aminoquinolines and Other Weak Bases: Mechanistic Studies

Lori Manzel, Lucjan Strekowski, Fyaz M. D. Ismail, Jerry C. Smith and Donald E. Macfarlane
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1337-1347;
Lori Manzel
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Lucjan Strekowski
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Fyaz M. D. Ismail
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Jerry C. Smith
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Donald E. Macfarlane
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Abstract

Oligodeoxynucleotides with unmethylated CpG motifs are immunostimulatory. Chloroquine and a number of structural analogs specifically and powerfully inhibit this effect at nanomolar concentrations. We explored the mechanism of this inhibition, with 4-aminoquinolines, quinacrine, 9-aminoacridines, and novel dibasic analogs, many of which are fluorescent. WEHI 231 murine B-lymphoma cells accumulated analogs up to a concentration several hundredfold higher than the medium. Uptake was rapid, nonsaturable, reversible, and partially inhibited by monensin, an agent that collapses pH gradients within cells. Uptake did not correlate highly with efficacy as inhibitors of CpG-oligodeoxynucleotide (ODN)-induced effects, suggesting that analogs act by a specific action. Confocal microscopy revealed analogs concentrating in large peripheral organelles. CpG-ODN is taken up by cells into acidifed, small, perinuclear vesicles. This uptake is thought to be necessary for immunostimulatory activity. Cellular uptake of fluorescent CpG-ODN was not inhibited by the analogs. The pH of intracellular CpG-ODN (6.4) was not affected by analogs at the concentration required for inhibition, but pH was increased by higher concentrations. UV spectroscopy revealed no binding of analogs to CpG-ODN. Nuclear Overhauser effect spectroscopy revealed that an analog bound to phosphatidylcholine vesicles, with the ring structure of the analog buried within the lipid and the side chain facing the aqueous environment. We conclude that the analogs do not inhibit the action of CpG-ODN by preventing the uptake or acidification of CpG-ODN. It seems more likely that the analogs inhibit the efficacy of CpG-ODN by a specific action within acidified vesicles, possibly at the interface of a phospholipid membrane.

Footnotes

  • Send reprint requests to: Donald E. Macfarlane, Department of Medicine, C32 GH, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242. E-mail: donald-macfarlane{at}uiowa.edu

  • ↵1 This work was supported by a Merit Review grant (to D.E.M.), and a grant (to L.S.) from the Petroleum Research Fund, administered by the American Chemical Society.

  • ↵2 Current address: Department of Chemistry, Georgia State University, Atlanta, GA 30303.

  • ↵3 Current address: Department of Physical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, Hertfordshire, UK.

  • Abbreviations:
    CpG-ODN
    oligodeoxynucleotide containing one or more immunostimulatory CpG sequences
    NOESY
    nuclear Overhauser effect spectroscopy
    DMPC
    1,2-dimyristoyl-sn-glycero-3-phosphocholine
    • Received May 6, 1999.
    • Accepted July 20, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Antagonism of Immunostimulatory CpG-Oligodeoxynucleotides by 4-Aminoquinolines and Other Weak Bases: Mechanistic Studies

Lori Manzel, Lucjan Strekowski, Fyaz M. D. Ismail, Jerry C. Smith and Donald E. Macfarlane
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1337-1347;

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Research ArticleArticle

Antagonism of Immunostimulatory CpG-Oligodeoxynucleotides by 4-Aminoquinolines and Other Weak Bases: Mechanistic Studies

Lori Manzel, Lucjan Strekowski, Fyaz M. D. Ismail, Jerry C. Smith and Donald E. Macfarlane
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1337-1347;
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