Phosphorothioate backbone modification modulates macrophage activation by CpG DNA1

Sester, D. P., Naik, S., Beasley, S. J., Hume, D. A. and Stacey, K. J. (2000) Phosphorothioate backbone modification modulates macrophage activation by CpG DNA1. The Journal of Immunology, 165 8: 4165-4173. doi:10.4049/jimmunol.165.8.4165

Author Sester, D. P.
Naik, S.
Beasley, S. J.
Hume, D. A.
Stacey, K. J.
Title Phosphorothioate backbone modification modulates macrophage activation by CpG DNA1
Journal name The Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2000-01-01
Sub-type Article (original research)
DOI 10.4049/jimmunol.165.8.4165
Open Access Status Not yet assessed
Volume 165
Issue 8
Start page 4165
End page 4173
Total pages 9
Place of publication Maryland, USA
Publisher The American Assn of Immunologists
Language eng
Subject C1
270100 Biochemistry and Cell Biology
780105 Biological sciences
Abstract Macrophages respond to unmethylated CpG motifs present in nonmammalian DNA. Stabilized phosphorothioate-modified oligodeoxynucleotides (PS-ODN) containing CpG motifs form the basis of immunotherapeutic agents. In this study, we show that PS-ODN do not perfectly mimic native DNA in activation of macrophages. CpG-containing PS-ODN were active at 10- to 100-fold lower concentrations than corresponding phosphodiester ODN in maintenance of cell viability in the absence of CSF-1, in induction of NO production, and in activation of the IL-12 promoter. These enhancing effects are attributable to both increased stability and rate of uptake of the PS-ODN. By contrast, PS-ODN were almost inactive in down-modulation of the CSF-1R from primary macrophages and activation of the HIV-1 LTR. Delayed or poor activation of signaling components may contribute to this, as PS-ODN were slower and less effective at inducing phosphorylation of the extracellular signal-related kinases 1 and 2. In addition, at high concentrations, non-CpG PS-ODN specifically inhibited responses to CpG DNA, whereas nonstimulatory phosphodiester ODN had no such effect. Although nonstimulatory PS-ODN caused some inhibition of ODN uptake, this did not adequately explain the levels of inhibition of activity. The results demonstrate that the phosphorothioate backbone has both enhancing and inhibitory effects on macrophage responses to CpG DNA.
Q-Index Code C1
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 102 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 10 Jun 2008, 22:59:29 EST