Inhibitors of TLR8 reduce TNF production from human rheumatoid synovial membrane cultures

Sacre, Sandra M, Lo, Alexandra, Gregory, Bernard, Simmonds, Rachel E, Williams, Lynn, Feldmann, Marc, Brennan, Fionula M and Foxwell, Brian M (2008) Inhibitors of TLR8 reduce TNF production from human rheumatoid synovial membrane cultures. Journal of Immunology, 181 (11). pp. 8002-8009. ISSN 0022-1767

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Abstract

The advent of anti-TNF biologicals has been a seminal advance in the treatment of rheumatoid arthritis (RA) and has confirmed the important role of TNF in disease pathogenesis. However, it is unknown what sustains the chronic production of TNF. In this study, we have investigated the anti-inflammatory properties of mianserin, a serotonin receptor antagonist. We discovered mianserin was able to inhibit the endosomal TLRs 3, 7, 8, and 9 in primary human cells and inhibited the spontaneous release of TNF and IL-6 from RA synovial membrane cultures. This suggested a role for these TLRs in production of TNF and IL-6 from RA which was supported by data from chloroquine, an inhibitor of endosomal acidification (a prerequisite for TLRs 3, 7, 8, and 9 activation) which also inhibited production of these cytokines from RA synovial cultures. Only stimulation of TLR 3 or 8 induced TNF from these cultures, indicating that TLR7 and TLR9 were of less consequence in this model. The key observation that indicated the importance of TLR8 was the inhibition of spontaneous TNF production by imiquimod, which we discovered to be an inhibitor of TLR8. Together, these data suggest that TLR8 may play a role in driving TNF production in RA. Because this receptor can be inhibited by small m.w. molecules, it may prove to be an important therapeutic target.

Item Type: Article
Keywords: toll-like receptor, tumour necrosis factor, rheumatoid arthritis.
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: Q Science > QR Microbiology > QR0180 Immunology
Depositing User: Sandra Sacre
Date Deposited: 22 Aug 2011 14:35
Last Modified: 05 Oct 2017 18:27
URI: http://sro.sussex.ac.uk/id/eprint/7074
Google Scholar:24 Citations

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