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

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

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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.


Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging in part because of the complexities and interconnected nature of intracellular signaling networks that complicate the effects of pharmacological interventions. We characterized the kinase signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of “off-target” pathways in a manner dependent on stimulatory context. Inhibitors of p38, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor κB (NF-κB), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. This was mediated by the transcription factor CREB, which functions in part within a negative feedback loop in MAPK signaling. CREB activation was induced predominately by p38 in response to inflammatory stimuli, but by MEK in response to mitogenic stimuli; hence, the effects of drugs targeting p38 or MEK were markedly different in SFs cultured under mitogenic or inflammatory conditions. Together, these findings illustrate how stimulatory context can alter dominance in pathway cross-talk even for a fixed network topology, thereby providing a rationale for why p38 inhibitors deliver limited benefits in RA and demonstrating the need for careful consideration of p38-targeted drugs in inflammation-related disorders.

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