Phosphorothioate backbone modification modulates macrophage activation by CpG DNA
| Autor: | Sester, D. P., Naik, S., Shannon Beasley, Hume, D. A., Stacey, K. J. |
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| Jazyk: | angličtina |
| Rok vydání: | 2000 |
| Předmět: |
Cell Survival
Dose-Response Relationship Immunologic Down-Regulation Bone Marrow Cells Receptor Macrophage Colony-Stimulating Factor Nitric Oxide Cell Line Mice Adjuvants Immunologic Animals Humans Phosphorylation Promoter Regions Genetic HIV Long Terminal Repeat Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Tumor Necrosis Factor-alpha Macrophages hemic and immune systems DNA respiratory system Macrophage Activation Thionucleotides Interleukin-12 Organophosphates Gene Expression Regulation Oligodeoxyribonucleotides Nucleic Acid Conformation CpG Islands Mitogen-Activated Protein Kinases |
| Zdroj: | Sester, D P, Naik, S, Beasley, S J, Hume, D A & Stacey, K J 2000, ' Phosphorothioate backbone modification modulates macrophage activation by CpG DNA ', Journal of Immunology, vol. 165, no. 8, pp. 4165-73 . Scopus-Elsevier |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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