title: Oligodeoxynucleotide inhibition of Toll-like receptors 3, 7, 8, and 9 suppresses cytokine production in a human rheumatoid arthritis model.
abstract: Toll-like receptors (TLRs) are innate immune receptors that respond to both exogenous and endogenous stimuli and are suggested to contribute to the perpetuation of chronic inflammation associated with rheumatoid arthritis (RA). In particular, the endosomal TLRs 3, 7, 8, and 9 have more recently been postulated to be of importance in RA pathogenesis. In this study, pan inhibition of the endosomal TLRs by a phosphorothioate-modified inhibitory oligodeoxynucleotide (ODN) is demonstrated in primary human B cells, macrophages, and RA fibroblasts. Inhibition of TLR8 was of particular interest as TLR8 has been associated with RA pathogenesis in both human and murine arthritis models. ODN1411 competitively inhibited TLR8 signaling and was observed to directly bind to a purified TLR8 ectodomain, suggesting inhibition was through a direct interaction with the receptor. Addition of ODN1411 to human RA synovial membrane cultures significantly inhibited spontaneous cytokine production from these cultures, suggesting a potential role for one or more of the endosomal TLRs in inflammatory cytokine production in RA and the potential for inhibitory ODNs as novel therapies.
authors.affiliation: Brighton and Sussex Medical School, Brighton, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sacre
authors.affiliation: Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Oxford, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lo
authors.affiliation: Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Oxford, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gregory
authors.affiliation: Brighton and Sussex Medical School, Brighton, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Stephens
authors.affiliation: Brighton and Sussex Medical School, Brighton, UK.
authors.forename: Giselle
authors.initials: G
authors.lastname: Chamberlain
authors.affiliation: Department of Orthopaedics, Brighton and Sussex University Hospitals, Brighton, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Stott
authors.affiliation: Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Oxford, UK.
authors.forename: Fionula
authors.initials: F
authors.lastname: Brennan
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D011992:Endosomes / Q000276:immunology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007249:Inflammation; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000037:antagonists & inhibitors / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000276:immunology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D016207:Cytokines; D009838:Oligodeoxyribonucleotides; C439524:TNF protein, human; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha
keywords: Cytokines; Inflammation; Oligodeoxynucleotide; Rheumatoid arthritis; TNF; Toll-like receptor