Inhibition of murine dendritic cell activation by synthetic phosphorothioate oligodeoxynucleotides.
Depending on sequence and backbone structure, DNA can inhibit as well as stimulate immune responses. As previously shown, single-base phosphorothioate (Ps) oligodeoxynucleotides (ODN) can inhibit murine macrophage activation. To determine whether these compounds can also affect dendritic cells (DC), the effects of 30-mer Ps ODN (SdA, SdT, SdG, and SdC) on DC activation were assessed in an in vitro system. With DC preparations obtained from murine bone marrow cultured in granulocyte macrophage-colony stimulating factor, the Ps ODN blocked the production of interleukin-12 and nitric oxide induced by bacterial DNA, an immunostimulatory cytosine phosphate guanosine dinucleotide (CpG) ODN and lipopolysaccharide (LPS). Furthermore, these compounds inhibited up-regulation of costimulatory molecules CD40 and CD86 as well as major histocompatibility complex-II molecules, indicating an effect on DC maturation. Although the Ps ODN limited uptake of CpG ODN as assessed by flow cytometry, the Ps ODN did not affect LPS uptake, suggesting that these compounds inhibit DC responses by effects on downstream signaling pathways. Together, these observations extend the range of action of inhibitory ODN to DC and suggest a role of these compounds as immunomodulatory agents.
Zhu
Fu-Gang
FG
Medical Research Service, Durham Veterans Administration Hospital and Division of Rheumatology, Allergy and Clinical Immunology, Duke University Medical Center, Durham, North Carolina, USA.
Reich
Charles F
CF
Pisetsky
David S
DS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001854:Bone Marrow Cells; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007111:Immunity, Cellular / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D013873:Thionucleotides / Q000138:chemical synthesis / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides; D018664:Interleukin-12; D009569:Nitric Oxide