{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T16:11:32Z","timestamp":1758125492649},"reference-count":52,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2015,6,12]],"date-time":"2015-06-12T00:00:00Z","timestamp":1434067200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Respivert"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2015,8]]},"abstract":"Background and Purpose<\/jats:title>To investigate whether a narrow spectrum kinase inhibitor RV<\/jats:styled-content>1088, which simultaneously targets specific MAPKs<\/jats:styled-content>, S<\/jats:styled-content>rc and spleen tyrosine kinase (Syk), is more effective at inhibiting inflammatory signalling in rheumatoid arthritis (RA<\/jats:styled-content>) than single kinase inhibitors (SKIs<\/jats:styled-content>).<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>elisa<\/jats:sc>s were used to determine the efficacy of RV<\/jats:styled-content>1088, clinically relevant SKIs<\/jats:styled-content> and the pharmaceutical H<\/jats:styled-content>umira on pro\u2010inflammatory cytokine production by activated RA<\/jats:styled-content> synovial fibroblasts, primary human monocytes and macrophages, as well as spontaneous cytokine synthesis by synovial membrane cells from RA<\/jats:styled-content> patients. In human macrophages, RNAi<\/jats:styled-content> knockdown of individual kinases was used to reveal the effect of inhibition of kinase expression on cytokine synthesis.<\/jats:p><\/jats:sec>Key Results<\/jats:title>RV<\/jats:styled-content>1088 reduced TNF<\/jats:styled-content>\u2010\u03b1, IL<\/jats:styled-content>\u20106 and IL<\/jats:styled-content>\u20108 production in all individual activated cell types with low, nM<\/jats:styled-content>, IC<\/jats:styled-content>50<\/jats:sub>s. SKIs<\/jats:styled-content>, and combinations of SKIs<\/jats:styled-content>, were significantly less effective than RV<\/jats:styled-content>1088. RNAi<\/jats:styled-content> of specific kinases in macrophages also caused only modest inhibition of pro\u2010inflammatory cytokine production. RV<\/jats:styled-content>1088 was also significantly more effective at inhibiting IL<\/jats:styled-content>\u20106 and IL<\/jats:styled-content>\u20108 production by monocytes and RA<\/jats:styled-content> synovial fibroblasts compared with H<\/jats:styled-content>umira. Finally, RV<\/jats:styled-content>1088 was the only inhibitor that was effective in reducing TNF<\/jats:styled-content>\u2010\u03b1, IL<\/jats:styled-content>\u20106 and IL<\/jats:styled-content>\u20108 synthesis in RA<\/jats:styled-content> synovial membrane cells with low nM IC<\/jats:styled-content>50<\/jats:sub>s.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>This study demonstrates potent anti\u2010inflammatory effect of RV<\/jats:styled-content>1088, highlighting that distinct signalling pathways drive TNF<\/jats:styled-content>\u2010\u03b1, IL<\/jats:styled-content>\u20106 and IL<\/jats:styled-content>\u20108 production in the different cell types found in RA<\/jats:styled-content> joints. As such, targeting numerous signalling pathways simultaneously using RV<\/jats:styled-content>1088 could offer a more powerful method of reducing inflammation in RA<\/jats:styled-content> than targeting individual kinases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13170","type":"journal-article","created":{"date-parts":[[2015,4,17]],"date-time":"2015-04-17T10:22:49Z","timestamp":1429266169000},"page":"3805-3816","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Potent anti\u2010inflammatory effects of the narrow spectrum kinase inhibitor RV<\/scp>1088 on rheumatoid arthritis synovial membrane cells"],"prefix":"10.1111","volume":"172","author":[{"given":"Wing S","family":"To","sequence":"first","affiliation":[{"name":"The Kennedy Institute of Rheumatology Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan R","family":"Aungier","sequence":"additional","affiliation":[{"name":"The Kennedy Institute of Rheumatology Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison J","family":"Cartwright","sequence":"additional","affiliation":[{"name":"The Kennedy Institute of Rheumatology Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Ito","sequence":"additional","affiliation":[{"name":"Airway Disease National Heart and Lung Institute Imperial College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim S","family":"Midwood","sequence":"additional","affiliation":[{"name":"The Kennedy Institute of Rheumatology Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,6,12]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100625"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12449"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12451"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI36389"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-8411(89)90129-7"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61424-X"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2013.04.007"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","unstructured":"CharronC CoatesM ItoK(2011).Effects of Rv1088 a Novel Narrow Spectrum Kinase Inhibitor on Pro\u2010Inflammatory Cytokine Production In Epithelial Cells Isolated From Asthma and COPD. 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