Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
32
pubmed:dateCreated
2004-8-2
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
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
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
6
pubmed:volume
279
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
33071-8
pubmed:dateRevised
2007-11-14
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
pubmed:year
2004
pubmed:articleTitle
Necessity of oligonucleotide aggregation for toll-like receptor 9 activation.
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
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.