Basic Science
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
Georg Schett, Makiyeh Tohidast-Akrad,
Josef S. Smolen,
Beatrice Jahn Schmid, Carl-Walter Steiner, Peter Bitzan, Peter Zenz, Kurt Redlich, Qingbo Xu, Günter Steiner,
Makiyeh Tohidast-Akrad
Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria
Search for more papers by this authorCorresponding Author
Josef S. Smolen
University of Vienna, and Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria
Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1180 Vienna, AustriaSearch for more papers by this authorGünter Steiner
University of Vienna, and Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria
Search for more papers by this authorGeorg Schett, Makiyeh Tohidast-Akrad,
Josef S. Smolen,
Beatrice Jahn Schmid, Carl-Walter Steiner, Peter Bitzan, Peter Zenz, Kurt Redlich, Qingbo Xu, Günter Steiner,
Makiyeh Tohidast-Akrad
Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria
Search for more papers by this authorCorresponding Author
Josef S. Smolen
University of Vienna, and Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria
Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1180 Vienna, AustriaSearch for more papers by this authorGünter Steiner
University of Vienna, and Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria
Search for more papers by this authorFirst published: 26 March 2001
Citations: 294
Abstract
Objective
To investigate whether stress- and mitogen-activated protein kinases (SAPK/MAPK), such as extracellular signal–regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, are significantly activated in rheumatoid arthritis (RA) synovial tissue compared with their activation in degenerative joint disease; to assess the localization of SAPK/MAPK activation in rheumatoid synovial tissue; and to search for the factors leading to stress 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 cytokine-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 localized around synovial microvessels, JNK activation was localized around and within mononuclear cell infiltrates, and p38 MAPK activation was observed in the synovial lining layer and in synovial endothelial cells. Tumor necrosis factor α, interleukin-1 (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 chronic synovitis in RA, but not in degenerative joint disease. SAPK/MAPK signaling is found at distinct sites in the synovial tissue, is induced by proinflammatory cytokines, and could lead to the design of highly targeted therapies.
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