{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:19:02Z","timestamp":1768004342723,"version":"3.49.0"},"reference-count":47,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2010,6,29]],"date-time":"2010-06-29T00:00:00Z","timestamp":1277769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2010,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The activity of p38 MAPK regulates lipopolysaccharide (LPS)\u2013stimulated production of key proinflammatory cytokines such as tumor necrosis factor \u03b1 (TNF\u03b1). Consequently, p38 MAPK inhibitors have attracted considerable interest as potential treatments of rheumatoid arthritis (RA), and studies in murine models of arthritis have yielded promising results. However, the performance of several compounds in human clinical trials has been disappointing. At present, the reason for this poor performance is unclear. The aim of this study was to examine the effects of p38 inhibitors on both diseased and normal human tissue and cells, in order to test whether this kinase still plays a critical role in cytokine production under conditions of chronic inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Proinflammatory and antiinflammatory cytokine production was monitored after treatment of primary human monocytes, macrophages, and RA synovial membrane cultures with p38 MAPK inhibitor compounds. The following 3 inhibitors were used in these studies: SB\u2010203580 (inhibits the \u03b1 and \u03b2 isoforms), BIRB\u2010796 (inhibits the \u03b1, \u03b2, \u03b3, and \u03b4 isoforms), and a novel, structurally distinct p38 MAPK inhibitor, SB\u2010731445 (inhibits the \u03b1 and \u03b2 isoforms).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SB\u2010731445 and SB\u2010203580 produced profound inhibition of spontaneous production of proinflammatory cytokines (TNF\u03b1 and interleukin\u20101 [IL\u20101]) in both RA membrane cultures and LPS\u2010stimulated primary human monocytes. However, this and other p38 MAPK inhibitors produced a significant increase in IL\u20106 production by LPS\u2010stimulated primary human macrophages and a decrease in IL\u201010 production by all cell types examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The potentially proinflammatory consequences of these activities (decreased IL\u201010 production and increased IL\u20106 production) may offer some explanation for the inability of p38 MAPK inhibitors to provide the therapeutic benefit that had been hoped for in RA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.27631","type":"journal-article","created":{"date-parts":[[2010,6,29]],"date-time":"2010-06-29T17:34:10Z","timestamp":1277832850000},"page":"3221-3231","source":"Crossref","is-referenced-by-count":31,"title":["Inhibitors of p38 suppress cytokine production in rheumatoid arthritis synovial membranes: Does variable inhibition of interleukin\u20106 production limit effectiveness in vivo?"],"prefix":"10.1002","volume":"62","author":[{"given":"Theresa H.","family":"Page","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Brown","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma M.","family":"Timms","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian M. 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