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To investigate whether a narrow spectrum kinase inhibitor RV1088, which simultaneously targets specific MAPKs, Src and spleen tyrosine kinase (Syk), is more effective at inhibiting inflammatory signalling in rheumatoid arthritis (RA) than single kinase inhibitors (SKIs).elisas were used to determine the efficacy of RV1088, clinically relevant SKIs and the pharmaceutical Humira on pro-inflammatory cytokine production by activated RA synovial fibroblasts, primary human monocytes and macrophages, as well as spontaneous cytokine synthesis by synovial membrane cells from RA patients. In human macrophages, RNAi knockdown of individual kinases was used to reveal the effect of inhibition of kinase expression on cytokine synthesis.RV1088 reduced TNF-α, IL-6 and IL-8 production in all individual activated cell types with low, nM, IC50 s. SKIs, and combinations of SKIs, were significantly less effective than RV1088. RNAi of specific kinases in macrophages also caused only modest inhibition of pro-inflammatory cytokine production. RV1088 was also significantly more effective at inhibiting IL-6 and IL-8 production by monocytes and RA synovial fibroblasts compared with Humira. Finally, RV1088 was the only inhibitor that was effective in reducing TNF-α, IL-6 and IL-8 synthesis in RA synovial membrane cells with low nM IC50 s.This study demonstrates potent anti-inflammatory effect of RV1088, highlighting that distinct signalling pathways drive TNF-α, IL-6 and IL-8 production in the different cell types found in RA joints. As such, targeting numerous signalling pathways simultaneously using RV1088 could offer a more powerful method of reducing inflammation in RA than targeting individual kinases.

Original publication

DOI

10.1111/bph.13170

Type

Journal article

Journal

British journal of pharmacology

Publication Date

08/2015

Volume

172

Pages

3805 - 3816

Addresses

The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Keywords

Synovial Membrane, Monocytes, Macrophages, Humans, Arthritis, Rheumatoid, Acetamides, Urea, Oxazines, Piperidines, Pyrazoles, Pyridines, Pyrimidines, Pyrroles, Naphthalenes, Tumor Necrosis Factor-alpha, RNA, Small Interfering, Anti-Inflammatory Agents, Inflammation Mediators, Interleukin-8, Interleukin-6, Protein Kinase Inhibitors, Signal Transduction, Dose-Response Relationship, Drug, Primary Cell Culture, Dasatinib, Adalimumab