Dual or triple activation of TLR7, TLR8, and/or TLR9 by single-stranded oligoribonucleotides.
Nucleic Acid Ther
; 21(6): 423-36, 2011 Dec.
Article
em En
| MEDLINE
| ID: mdl-22196370
ABSTRACT
The toll-like receptors (TLRs) 7, 8, and 9 stimulate innate immune responses upon recognizing pathogen nucleic acids. Certain GU- or AU-rich RNA sequences were described to differentiate between human TLR7- and TLR8-mediated immune effects. Those single-stranded RNA molecules require endosomal delivery for stabilization against ribonucleases. We have discovered RNA sequences that preferentially activate TLR7, form higher ordered structures, and do not require specific cellular delivery. In addition, a dual activation of TLR8 and TLR9 without affecting TLR7 can be achieved by chimeric molecules consisting of GU-rich RNA and Cytosin (C) phosphordiester or phosphorthioat (p) guanine (CpG) motif DNA sequences. Such chimeras stimulate TLR9-mediated type I interferon (IFN) and TLR8-depending proinflammatory cytokine and chemokine production upon primary human cell activation. However, an RNA-dependent TLR7 IFN-α cytokine release is suppressed by the phosphorothioate DNA sequence contained in the chimeric molecule. To convert the immune response of a single-stranded RNA from TLR7/8 to TLR9, a simple chemical modification at the 5' end proves to be sufficient. Such 8-oxo-2'-deoxy-guanosine or 8-bromo-2'-deoxy-guanosine modifications of the first guanosine in GU-rich single-stranded RNAs convert the immune response to include TLR9 activation and demonstrate strong additive effects for type I IFN immune responses in human primary cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oligorribonucleotídeos
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Receptor Toll-Like 9
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Receptor 7 Toll-Like
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Receptor 8 Toll-Like
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Nucleic Acid Ther
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Alemanha