Inhibitors of TLR-9 act on multiple cell subsets in mouse and man in vitro and prevent death in vivo from systemic inflammation
| Autor: | Karen L. Fearon, Franck J. Barrat, Omar Duramad, Jean H. Chan, Josh Gregorio, Bonnie Chang, Robert L. Coffman |
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| Rok vydání: | 2005 |
| Předmět: |
Cell type
CpG Oligodeoxynucleotide Injections Subcutaneous Immunology Inflammation Receptors Cell Surface Cell Separation Biology Systemic inflammation Mice Adjuvants Immunologic In vivo Sepsis medicine Immunology and Allergy Animals Humans Mice Inbred BALB C Guanosine Anti-Inflammatory Agents Non-Steroidal Interferon-alpha Dendritic Cells Thionucleotides Molecular biology In vitro Lymphocyte Subsets Cell biology Interleukin-10 DNA-Binding Proteins Interleukin 10 CpG site Oligodeoxyribonucleotides Toll-Like Receptor 9 Leukocytes Mononuclear Nucleic Acid Conformation CpG Islands medicine.symptom Spleen |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 174(9) |
| ISSN: | 0022-1767 |
| Popis: | In parallel with the discovery of the immunostimulatory activities of CpG-containing oligodeoxynucleotides, several groups have reported specific DNA sequences that could inhibit activation by CpG-containing oligodeoxynucleotides in mouse models. We show that these inhibitory sequences, termed IRS, inhibit TLR-9-mediated activation in human as well as mouse cells. This inhibitory activity includes proliferation and IL-6 production by B cells, and IFN-α and IL-12 production by plasmacytoid dendritic cells. Our studies of multiple cell types in both mice and humans show the optimal IRS to contain a GGGG motif within the sequence, and the activity to require a phosphorothioate backbone. Although the GGGG motif readily itself leads to formation of a tetrameric oligodeoxynucleotide structure, inhibitory activity resides exclusively in the single-stranded form. When coinjected with a CpG oligodeoxynucleotide in vivo, IRS were shown to inhibit inflammation through a reduction in serum cytokine responses. IRS do not need to be injected at the same site to inhibit, demonstrating that rapid, systemic inhibition of TLR-9 can be readily achieved. IRS can also inhibit a complex pathological response to ISS, as shown by protection from death after massive systemic inflammation induced by a CpG-containing oligodeoxynucleotides. |
| Databáze: | OpenAIRE |
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