rdf:type |
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lifeskim:mentions |
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pubmed:issue |
32
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pubmed:dateCreated |
2004-8-2
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pubmed:abstractText |
Toll-like receptor 9 (TLR9), a member of the interleukin-1 (IL-1) family of pathogen-associated molecular pattern receptors, is activated by unmethylated CpG-containing sequences in bacterial DNA or synthetic oligonucleotides (ODNs) in the endosomal compartment. The stimulation of an IL-1 response is thought to require the aggregation of its receptor. By analogy, we postulated that the potency of a TLR9 ligand should depend first on its ability to enter cells and gain access to TLR9 and second on its capacity to form a multimeric complex capable of cross-linking these receptors. Previously, we selected from a random library a series of phosphodiester ODNs with enhanced ability to permeate cells. Here, we studied the structural requirements for these penetrating ODNs to elicit a functional TLR9 response, as assessed by cytokine production from bone marrow-derived mouse mononuclear cells. The presence of a prototypic murine immunostimulatory DNA hexameric sequence (purine-purine-CG-pyrimidine-pyrimidine) in the ODNs was not sufficient for stimulation. In addition, the TLR9-activating ODNs had to have the ability to form aggregates and often to form secondary structures near the core CpG motifs. Multimerization was promoted by the presence of a guanine-rich 3'-terminus. The phosphodiester ODNs with CpG motifs that did not aggregate antagonized the effects of the multimeric TLR9 activators. These findings suggest that an optimal TLR9 agonist needs to contain a spatially distinct multimerization domain and a receptor binding CpG domain. This concept may prove useful for the design of new TLR9-modulating agents.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Differentiation,
http://linkedlifedata.com/resource/pubmed/chemical/Cross-Linking Reagents,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-12,
http://linkedlifedata.com/resource/pubmed/chemical/Myd88 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Myeloid Differentiation Factor 88,
http://linkedlifedata.com/resource/pubmed/chemical/Oligodeoxyribonucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cell Surface,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Immunologic,
http://linkedlifedata.com/resource/pubmed/chemical/Tlr9 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Toll-Like Receptor 9
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
6
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pubmed:volume |
279
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
33071-8
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:15184382-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:15184382-Animals,
pubmed-meshheading:15184382-Antigens, Differentiation,
pubmed-meshheading:15184382-Base Sequence,
pubmed-meshheading:15184382-Bone Marrow Cells,
pubmed-meshheading:15184382-Cells, Cultured,
pubmed-meshheading:15184382-Cross-Linking Reagents,
pubmed-meshheading:15184382-DNA,
pubmed-meshheading:15184382-DNA-Binding Proteins,
pubmed-meshheading:15184382-Interleukin-12,
pubmed-meshheading:15184382-Mice,
pubmed-meshheading:15184382-Mice, Inbred BALB C,
pubmed-meshheading:15184382-Mice, Inbred C57BL,
pubmed-meshheading:15184382-Mice, Knockout,
pubmed-meshheading:15184382-Myeloid Differentiation Factor 88,
pubmed-meshheading:15184382-Nucleic Acid Conformation,
pubmed-meshheading:15184382-Oligodeoxyribonucleotides,
pubmed-meshheading:15184382-Receptors, Cell Surface,
pubmed-meshheading:15184382-Receptors, Immunologic,
pubmed-meshheading:15184382-Structure-Activity Relationship,
pubmed-meshheading:15184382-Toll-Like Receptor 9
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pubmed:year |
2004
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pubmed:articleTitle |
Necessity of oligonucleotide aggregation for toll-like receptor 9 activation.
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pubmed:affiliation |
Division of Rheumatology Allergy and Immunology, Department of Medicine and the Sam and Rose Stein Institute for Research on Aging, University of California San Diego, La Jolla, California 92093-0663, USA. c5wu@ucsd.edu
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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