Inhibitors of p38 suppress cytokine production in rheumatoid arthritis synovial membranes: does variable inhibition of interleukin-6 production limit effectiveness in vivo?

Arthritis Rheum 62(11):3221-31 (2010) PMID 20589681

The activity of p38 MAPK regulates lipopolysaccharide (LPS)-stimulated production of key proinflammatory cytokines such as tumor necrosis factor α (TNFα). 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.