Binding of Oligoguanylate to Scavenger Receptors Is Required for Oligonucleotides to Augment NK Cell Activity and Induce IFN

Kimura, Yasuto; Sonehara, Kazuhiko; Kuramoto, Etsuro; Makino, T.; Yamamoto, Saburo; Yamamoto, Toshiko; Kataoka, Tateshi; Tokunaga, Tohru

doi:10.1093/oxfordjournals.jbchem.a124658

Cited by 122 publications

(70 citation statements)

References 17 publications

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“…5 Indeed, previous studies have suggested that binding of oligos to the scavenger receptors is required for their immune stimulatory activities and that scavenger receptor competitors such as poly-Gs and fucoidan are inhibitory on the immune activation by EC and CpG ODN. [19][20][21] Several experiments were performed to explore the possibility of uptake inhibition in more detail. First of all, EC and CT DNA were mixed at a 1:1 ratio starting from 4 g/ml and the mixture was serially diluted.…”

Section: Resultsmentioning

confidence: 99%

Identification of methylated CpG motifs as inhibitors of the immune stimulatory CpG motifs

et al. 2001

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The unmethylated CpG motifs within E. coli DNA (EC) cause immune stimulation. In contrast, mammalian DNA such as calf thymus (CT) DNA had been thought to be immunologically inert. In this article, we demonstrate that CT DNA unexpectedly specifically inhibits the immune activation by EC but not that by endotoxin. This inhibitory effect was mediated in the signaling pathway activated by EC since CT DNA markedly inhibited the CpG-induced nuclear translocation of the transcription factors, NF-B and AP-1. In addition, CT DNA significantly inhibited the synergistic immune activation by EC and endotoxin. The mechanism of the inhibition by CT DNA probably did not involve the inhi-

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Section: Resultsmentioning

confidence: 99%

Identification of methylated CpG motifs as inhibitors of the immune stimulatory CpG motifs

et al. 2001

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“…Oligo-dG sequences have complex effects on cells, including formation of macrophage-like colonies from bone marrow (30), inhibition of tumor cell growth (31), and costimulation of T cells (3) in addition to inhibition of macrophage responses to CpG DNA (14,22). Inclusion of dG runs in ODN may enhance their uptake by scavenger receptor (32), but it would be unwise to assume that all effects of oligo-dG are mediated by this receptor, as other proteins, such as a macrophage cytoplasmic protein, have shown preferential binding to G-rich ODN (30). Inhibition by runs of dG nucleotides probably also explains the inhibition of macrophage activation observed by Häcker et al (33), and their claim that inhibition was sequence independent may have been due to the confounding effects of PS-specific inhibition at higher concentrations (28).…”

Section: Discussionmentioning

confidence: 99%

The Molecular Basis for the Lack of Immunostimulatory Activity of Vertebrate DNA

Stacey

Young

Clark

et al. 2003

The Journal of Immunology

165

193

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Macrophages and B cells are activated by unmethylated CpG-containing sequences in bacterial DNA. The lack of activity of self DNA has generally been attributed to CpG suppression and methylation, although the role of methylation is in doubt. The frequency of CpG in the mouse genome is 12.5% of Escherichia coli, with unmethylated CpG occurring at ∼3% the frequency of E. coli. This suppression of CpG alone is insufficient to explain the inactivity of self DNA; vertebrate DNA was inactive at 100 μg/ml, 3000 times the concentration at which E. coli DNA activity was observed. We sought to resolve why self DNA does not activate macrophages. Known active CpG motifs occurred in the mouse genome at 18% of random occurrence, similar to general CpG suppression. To examine the contribution of methylation, genomic DNAs were PCR amplified. Removal of methylation from the mouse genome revealed activity that was 23-fold lower than E. coli DNA, although there is only a 7-fold lower frequency of known active CpG motifs in the mouse genome. This discrepancy may be explained by G-rich sequences such as GGAGGGG, which potently inhibited activation and are found in greater frequency in the mouse than the E. coli genome. In summary, general CpG suppression, CpG methylation, inhibitory motifs, and saturable DNA uptake combined to explain the inactivity of self DNA. The immunostimulatory activity of DNA is determined by the frequency of unmethylated stimulatory sequences within an individual DNA strand and the ratio of stimulatory to inhibitory sequences.

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“…In some circumstances, nucleic acid-binding receptors may play a role in stimulation by sODNs. Thus, runs of guanine (G), which can bind to the type I scavenger receptor by forming base-quartet-stabilized four-stranded helices, can promote the activity of stimulatory ODN for macrophages and lead to enhanced NK cell lytic activity and IFN-␥ production (25,26). Other cell surface molecules may also function as ODN receptors.…”

Section: Discussionmentioning

confidence: 99%

The Role of Cell Surface Receptors in the Activation of Human B Cells by Phosphorothioate Oligonucleotides

Liang

Reich

Pisetsky

et al. 2000

The Journal of Immunology

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Phosphorothioate oligodeoxynucleotides (sODN) containing the CpG motif or TCG repeats induce T cell-independent polyclonal activation of human B cells. To elucidate the mechanism of this response, the role of cell surface receptors was investigated. Sepharose beads coated with stimulatory but not nonstimulatory sODNs induced B cell proliferation comparably with soluble sODNs. The B cell stimulatory activity of Sepharose-bound sODN did not result from free sODN released from the beads since media incubated with coated beads were inactive. Using FITC-labeled sODNs as probes, binding to human B cells could be detected by flow cytometry. Binding was rapid, saturable, initially temperature independent, but with a rapid off-rate. Competition studies indicated that both stimulatory sODNs and minimally stimulatory sODNs bound to the same receptor. By contrast, phosphodiester oligonucleotides with the same nucleotide sequence as sODNs and bacterial DNA inhibited the binding of sODNs to B cells minimally. Charge appeared to contribute to the binding of sODNs to B cells since binding of sODNs was competitively inhibited by negatively charged molecules, including fucoidan, poly I, and polyvinyl sulfate. These data indicate that human B cells bind sODNs by a receptor-mediated mechanism that is necessary but not sufficient for polyclonal activation.

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Binding of Oligoguanylate to Scavenger Receptors Is Required for Oligonucleotides to Augment NK Cell Activity and Induce IFN

Cited by 122 publications

References 17 publications

Identification of methylated CpG motifs as inhibitors of the immune stimulatory CpG motifs

Identification of methylated CpG motifs as inhibitors of the immune stimulatory CpG motifs

The Molecular Basis for the Lack of Immunostimulatory Activity of Vertebrate DNA

The Role of Cell Surface Receptors in the Activation of Human B Cells by Phosphorothioate Oligonucleotides

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