| Activation and regulation of toll-like receptor 9: CpGs and beyond. | |
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MedLine Citation:
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PMID: 18537714 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Toll-like receptor 9 has been the focus of considerable research attention for the ability to modulate its activity, and subsequent innate immune responses, through DNA-based immunotherapeutics. Nucleic acids are attractive as therapeutics for their low cost, chemical stability and ease of production. While the ability for TLR9 to be differentially regulated by nucleic acids of varying sequences and structures offers flexibility for immunotherapeutic design, it also necessitates a more comprehensive characterization of these agonists in terms of how these structural parameters correlate with the activation of unique cellular responses. Despite the utilization of TLR9 agonists in human trials these issues have not been adequately addressed. While a wealth of cell stimulation experiments demonstrate the preferential ability for nucleic acids which contain unmethylated cytosine-phosphate-guanine (CpG) motifs to initiate innate immune responses this has not been supported by binding investigations from which largely contradictory information has emerged with respect to the ability of TLR9 to bind nucleic acids in a sequence-dependent fashion. Recent models help to reconcile this apparent contradiction by suggesting that while TLR9 activation is specific for CpG-containing nucleic acids, the receptor binds, and is functionally influenced by, nucleic acids in a sequence-independent fashion. We have proposed a model in which the absolute concentration of nucleic acids modulates the sensitivity of the receptor in a sequence-dependent fashion while activation is specifically achieved by CpG-containing ligands. In this review we reconsider the literature from the perspective of this new appreciation of the functional complexity of TLR9 ligand binding and higher-order regulation with discussion of the implications for immunotherapeutic targeting of TLR9. |
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Authors:
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Jason Kindrachuk; Jean Potter; Heather L Wilson; Philip Griebel; Lorne A Babiuk; Scott Napper |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Review |
Journal Detail:
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Title: Mini reviews in medicinal chemistry Volume: 8 ISSN: 1389-5575 ISO Abbreviation: Mini Rev Med Chem Publication Date: 2008 Jun |
Date Detail:
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Created Date: 2008-06-09 Completed Date: 2008-08-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101094212 Medline TA: Mini Rev Med Chem Country: Netherlands |
Other Details:
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Languages: eng Pagination: 590-600 Citation Subset: IM |
Affiliation:
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Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E3, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals CpG Islands / physiology* Humans Models, Biological* Signal Transduction Toll-Like Receptor 9 / physiology* Up-Regulation |
| Chemical | |
Reg. No./Substance:
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0/Toll-Like Receptor 9 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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