Therapeutic regulation of cytokine signalling by inhibitors of p38 mitogen-activated protein kinase

Over the last four years, selective inhibitors of the enzyme p38 mitogen-activated protein kinase (p38 MAPK) have emerged as potential new drugs for the treatment of inflammatory diseases, such as rheumatoid arthritis. Inhibition of the kinase activity of p38 MAPK is associated with the modulation of cytokine production, in particular tumor necrosis factor (TNF) and interleukin-1 (IL-1), and also the response of cells to these pro-inflammatory agents. This profile suggests that inhibitors of p38 MAPK may be disease-modifying, hence this enzyme has become the focus of considerable activity in the pharmaceutical industry. In this chapter we will review the chemistry and biology of p38 MAPK inhibitors and discuss how blocking the activity of p38 MAPK leads to an anti-inflammatory effect.