Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis

Objective, To investigate whether stress- and mitogen-activated protein kin ases (SAPK/MAPK), such as extracellular signal-regulated kinase (ERK), c-Ju n N-terminal kinase (JNK), and p38 MAPK, are significantly activated in rhe umatoid arthritis (RA) synovial tissue compared with their activation in de generative joint disease; to assess the localization of SAPK/MAPK activatio n in rheumatoid synovial tissue; and to search for the factors leading to s tress kinase activation in human synovial cells, Methods. Immunoblotting and immunohistology by antibodies specific for the activated forms of SAPK/MAPK were performed on synovial tissue samples from patients with RA and osteoarthritis (OA), In addition, untreated and cytok ine-treated human synovial cells were assessed for SAPK/MAPK activation and downstream signaling by various techniques, Results, ERK, JNK, and p38 MAPK activation were almost exclusively found in synovial tissue from RA, but not OA, patients, ERK activation was localize d around synovial microvessels, JNK activation was localized around and wit hin mononuclear cell infiltrates, and p38 MAPK activation was observed in t he synovial lining layer and in synovial endothelial cells. Tumor necrosis factor alpha, interleukin-l (IL-1), and IL-6 were the major inducers of ERK , JNK, and p38 MAPK activation in cultured human synovial cells. Conclusion, Signaling through SAPK/MAPK pathways is a typical feature of ch ronic synovitis in RA, but not in degenerative joint disease, SAPK/MAPK sig naling is found at distinct sites in the synovial tissue, is induced by pro inflammatory cytokines, and could lead to the design of highly targeted the rapies.