title: Toll-like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR-mediated effects).
abstract: The Toll-like receptors (TLRs) 3, 7, 8 and 9 stimulate innate immune responses upon recognizing pathogen-derived nucleic acids. TLR3 is located on the cell surface and in cellular endosomes and recognizes double-stranded viral RNA or the synthetic mimic poly rI:rC. Recently, unformulated small interfering RNA (siRNA) has been reported as ligand for surface-expressed murine TLR3. Blockage of TLR3 is achieved by single-stranded DNA. We confirm and expand the observation that poly rI:rC-mediated TLR3 immune activation is blocked in a sequence-, length-, backbone- and CpG-dependent manner. However, human TLR3 is not activated by siRNA, which may be the result of differences in the amino acid composition of the TLR3 loop 1 of mice and humans. Although CD14 was previously described as a co-receptor for murine TLR3 and other nucleic acid-recognizing TLRs, human CD14 acts only as co-receptor to human TLR9, but not TLR3, TLR7 or TLR8. We show that CD14 up-regulates the TLR9 immune response of A, B and C-class oligodeoxynucleotides but down-regulates the phosphoro-diester version of B-class oligodeoxynucleotides.
authors.affiliation: Pfizer Oligonucleotide Therapeutics Unit - Coley Pharmaceutical GmbH, Merowingerplatz 1a, 40225 Düsseldorf, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Weber
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.forename: Anja
authors.initials: A
authors.lastname: Podszuweit
authors.forename: Carmen
authors.initials: C
authors.lastname: Montino
authors.forename: Jörg
authors.initials: J
authors.lastname: Vollmer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Forsbach
mesh_terms: D000818:Animals; D002460:Cell Line; D004277:DNA, Single-Stranded / Q000235:genetics*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: D004277:DNA, Single-Stranded; D018950:Lipopolysaccharide Receptors; D034741:RNA, Small Interfering; C495344:TLR3 protein, human; C495371:TLR9 protein, human; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9