title: Negative regulation of the type I interferon signaling pathway by synthetic Toll-like receptor 7 ligands.
abstract: Ten Toll-like receptor (TLR) family members have been reported in humans. Here, the endoplasmatic receptors TLR9, TLR8, TLR7, and TLR3 respond to nucleic acids and derivatives or to small molecules (TLR7 and 8). Another cytoplasmic RNA receptor, retinoic acid inducible gene I (RIG-I), is stimulated by 5' triphosphate double-stranded RNA. We discovered that TLR7 small-molecule agonists inhibit nucleic acid-mediated TLR3, TLR7, TLR9, or RIG-I-dependent interferon-α (IFN-α) immune response. Other cytokines and chemokines stimulated by nucleic acid agonists remained unaffected. The observed blockage of TLR3, TLR7, TLR9, and RIG-I-mediated IFN-α response appears to be driven by a competitive mechanism at the type I IFN pathway. Besides type I IFN, IFN response genes such as IFIT-1, Mx1, OAS1, or IRF7 were affected, which indicates that the key element driving the inhibition is located in the type I IFN pathway. Indeed, the heterotrimeric complex formation of phosphor-signal transducer and activator of transcription factor 1 (STAT1), phosphor-STAT2, and IRF9 (called ISGF3, IFN-stimulated gene factor 3) is inhibited through the TLR7 small-molecule agonists by phosphor-STAT2 blockage. These findings provide novel insights into the use of synthetic TLR7 or TLR7/8 small molecules as ligands for immune activation and suppression.
authors.affiliation: Pfizer Oligonucleotide Therapeutics Unit-Coley Pharmaceutical GmbH , Düsseldorf, Germany. aforsbach@gmx.de
authors.forename: Alexandra
authors.initials: A
authors.lastname: Forsbach
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.forename: Carmen
authors.initials: C
authors.lastname: Montino
authors.forename: Andrea
authors.initials: A
authors.lastname: Kritzler
authors.forename: Toan
authors.initials: T
authors.lastname: Nguyen
authors.forename: Risini
authors.initials: R
authors.lastname: Weeratna
authors.forename: Marion
authors.initials: M
authors.lastname: Jurk
authors.forename: Jörg
authors.initials: J
authors.lastname: Vollmer
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010766:Phosphorylation; D050795:STAT2 Transcription Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D008024:Ligands; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7