Open AccessInhibition of NF‐κB signaling by fasudil as a potential therapeutic strategy for rheumatoid arthritis
Author(s) -
Okamoto Hiroshi,
Yoshio Taku,
Kaneko Hirotaka,
Yamanaka Hisashi
Publication year - 2010
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.25063
Subject(s) - fasudil , cytokine , arthritis , pharmacology , rheumatoid arthritis , medicine , chemistry , signal transduction , immunology , cancer research , rho associated protein kinase , biochemistry
Abstract Objective Rheumatoid arthritis (RA) is the most common systemic autoimmune disease and is characterized mainly by symmetric polyarticular joint disorders. The pathologic processes are mediated by a number of cytokines, chemokines, cell adhesion molecules, and matrix metalloproteinases. The expression of most of these molecules is controlled at the transcriptional level. In addition, activation of NF‐κB is involved in RA pathogenesis. This study was performed to explore the role of a novel serine/threonine kinase inhibitor, fasudil, in the control of the NF‐κB activation pathway and to investigate the therapeutic effects of fasudil on arthritis development in a rat model of RA. Methods Fibroblast‐like synoviocytes (FLS) from RA patients and human endothelial cells (ECs) were established and maintained. To study the role of fasudil on cytokine expression, various cytokines expressed in the RA FLS and human ECs were measured by enzyme‐linked immunosorbent assay following stimulation of the cells with interleukin‐1β (IL‐1β) in the presence of various concentrations of fasudil. The role of fasudil on NF‐κB activation was studied using a reporter gene assay, Western blotting of IκBα, immunofluorescence analysis of the p65 subunit of NF‐κB, and electrophoretic mobility shift assay. The in vivo effects of fasudil on arthritis were studied in a rat adjuvant‐induced arthritis (AIA) model. Results Fasudil inhibited cytokine expression in RA FLS and human ECs and also inhibited the activation of ECs, in a dose‐dependent manner. Fasudil inhibited IL‐1β–induced activation of NF‐κB independent of the inhibition of IκBα degradation and nuclear translocation of NF‐κB, and inhibited IL‐1β–induced DNA binding of NF‐κB. Finally, in vivo, fasudil ameliorated arthritis in rats with AIA, without any adverse effects. Conclusion Serine/threonine kinase inhibitor fasudil inhibits the development of arthritis in a rat model of RA, and also inhibits the NF‐κB signaling required for binding of NF‐κB to specific DNA sequences through, for example, the phosphorylation of p65, suggesting that a specific target of fasudil might be a novel NF‐κB kinase. Thus, fasudil serves as a novel strategy for the treatment of RA.