Kennedy Institute of Rheumatology Division, Imperial College London, 65 Aspenlea Road, Hammersmith, London W6 8LH, UK
The p38 mitogen-activated protein kinase (MAPK) signaling pathway has been strongly implicated in many of
the processes that underlie the pathology of rheumatoid arthritis (RA). For many years it has been considered a promising
target for development of new anti-inflammatory drugs with which to treat RA and other chronic immune-mediated
inflammatory diseases. However, several recent clinical trials have concluded in a disappointing manner. Why is this so, if
p38 MAPK clearly contributes to the excessive production of inflammatory mediators, the destruction of bone and
cartilage? We argue that, to explain the apparent failure of p38 inhibitors in the rheumatology clinic, we need to
understand better the complexities of the p38 pathway and its many levels of communication with other cellular signaling
pathways. In this review we look at the p38 MAPK pathway from a slightly different perspective, emphasising its role in
post-transcriptional rather than transcriptional control of gene expression, and its contribution to the off-phase rather than
the on-phase of the inflammatory response.
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