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Impact of site-specific nucleobase deletions on the arthritogenicity of DNA

Bjersing, Jan, 1966 (author)
Gothenburg University,Göteborgs universitet,Institutionen för invärtesmedicin, Avdelningen för reumatologi och inflammationsforskning,Institute of Internal Medicine, Dept of Rheumatology and Inflammation Research
Tarkowski, Andrej, 1951 (author)
Gothenburg University,Göteborgs universitet,Institutionen för invärtesmedicin, Avdelningen för reumatologi och inflammationsforskning,Institute of Internal Medicine, Dept of Rheumatology and Inflammation Research
Kandimalla, E. R. (author)
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Karlsson, H. (author)
Agrawal, S. (author)
Collins, Vincent, 1962 (author)
Gothenburg University,Göteborgs universitet,Institutionen för invärtesmedicin, Avdelningen för reumatologi och inflammationsforskning,Institute of Internal Medicine, Dept of Rheumatology and Inflammation Research
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 (creator_code:org_t)
2004
2004
English.
In: Inflammation. - 0360-3997. ; 28:3, s. 159-68
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Oligodeoxynucleotides (ODN) containing unmethylated CpG motifs (CpG ODN) potently stimulate the innate and acquired immune system. We have compared the in vivo and in vitro inflammatogenic properties of CpG ODNs containing a specific nucleobase deletion either 5'-upstream (ODN-2) or 3'-downstream (ODN-3) of the CpG motif, comparing with a prototype CpG ODN (ODN-1). The frequency of arthritis was similar after intra-articular (i.a.) injections of ODN-1 or ODN-3, but was significantly lower (p < 0.02) after i.a. injections of ODN-2. In vitro production of the pro-inflammatory cytokine TNF-alpha was higher in mouse spleen cell cultures exposed to ODN-2 in comparison to ODN-1. In addition, the level of IL-10 induced by ODN-2 was higher than that induced by ODN-1. On the other hand, TNF-alpha, IL-10, and MCP-1 levels, as well as splenocyte proliferative responses were all significantly lower for ODN-3 than for ODN-1. These results suggest that a 5'-upstream nucleobase deletion reduces arthritogenicity, while maintaining or increasing the production of pro- and anti-inflammatory factors. In contrast, a 3'-downstream nucleobase deletion has no effect on arthritogenicity, despite significantly lower levels of proliferation and pro- and anti-inflammatory cytokines, compared with ODN-1. This study indicates that specific structural elements within the ODN sequence but outside the CpG motif, modulate the immunostimulatory properties of CpG ODNs.

Keyword

Animals
Arthritis/chemically induced/*genetics
Base Sequence
Cell Proliferation/drug effects
Cells
Cultured
Chemokines/biosynthesis
CpG Islands
Cytokines/biosynthesis
DNA/*genetics/*toxicity
Female
Lymphocyte Activation/drug effects
Mice
Oligodeoxyribonucleotides/genetics/toxicity
Sequence Deletion/*genetics
Spleen/cytology/metabolism

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ref (subject category)
art (subject category)

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