Oligodeoxynucleotide inhibition of Toll-like receptors 3, 7, 8, and 9 suppresses cytokine production in a human rheumatoid arthritis model

Sacre, Sandra, Lo, Alexandra, Gregory, Bernard, Stephens, Matthew, Chamberlain, Giselle, Stott, Philip and Brennan, Fionula (2016) Oligodeoxynucleotide inhibition of Toll-like receptors 3, 7, 8, and 9 suppresses cytokine production in a human rheumatoid arthritis model. European Journal of Immunology, 46 (3). pp. 772-81. ISSN 1521-4141

[img] PDF (manuscript) - Accepted Version
Download (307kB)
[img] Image (TIFF) (figure1) - Accepted Version
Download (104kB)
[img] Image (TIFF) (figure2) - Accepted Version
Download (98kB)
[img] Image (TIFF) (figure3) - Accepted Version
Download (99kB)
[img] Image (TIFF) (figure 4) - Accepted Version
Download (185kB)
[img] Image (TIFF) (figure 5) - Accepted Version
Download (71kB)
[img] Image (TIFF) (figure 6) - Accepted Version
Download (109kB)

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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Laboratory Investigation
Subjects: Q Science
R Medicine
Depositing User: Sandra Sacre
Date Deposited: 31 Mar 2016 08:03
Last Modified: 02 Apr 2017 07:34
URI: http://sro.sussex.ac.uk/id/eprint/60167

View download statistics for this item

📧 Request an update