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Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures¹

Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by The Kennedy Institute of Rheumatology Trustees, The Arthritis Research Council, and Cornell University.

² Address correspondence and reprint requests to Dr. Brian M. Foxwell, Kennedy Institute of Rheumatology, 65 Aspenlea Road, Hammersmith, London W6 8LH, U.K. E-mail address: b.foxwell{at}imperial.ac.uk

³ Abbreviations used in this paper: RA, rheumatoid arthritis; RASF, RA synovial fibroblast; Mal, MyD88 adaptor-like; 5-HT, serotonin; poly(IC), polyinosinic-polycytidylic acid.