Research ArticleRHEUMATOID ARTHRITIS

Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition

See allHide authors and affiliations

Sci. Signal.  06 Mar 2018:
Vol. 11, Issue 520, eaal1601
DOI: 10.1126/scisignal.aal1601

You are currently viewing the editor's summary.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Context complicates network models

In rheumatoid arthritis (RA), inflammation is driven by the increased activity of the kinase p38 MAPK. However, p38 MAPK inhibitors are ineffective in patients. Using synovial fibroblasts and synovial fluid from RA patients, Jones et al. found that unlike cells in proliferative conditions, such as those in which cancer cells are grown (from which many network models have been built), p38 MAPK was a critical inducer of negative cross-talk to the MAPK-related, JNK pathway in cells grown in the inflammatory context associated with RA. Thus, inhibiting p38 facilitated JNK activity and the perpetuation of inflammatory cytokine production. Culturing the same cells under proliferative conditions switched the dominant point of negative cross-talk between the MAPK pathways to the kinase MEK. Inhibitors of the upstream kinase TAK1 curbed the activity of both the p38 and JNK pathways in the cells and, hence, might be effective in RA patients.