Abstract | OBJECTIVE: 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-1beta (IL-1beta) in the presence of various concentrations of fasudil. The role of fasudil on NF-kappaB activation was studied using a reporter gene assay, Western blotting of IkappaBalpha, immunofluorescence analysis of the p65 subunit of NF-kappaB, 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-1beta-induced activation of NF-kappaB independent of the inhibition of IkappaBalpha degradation and nuclear translocation of NF-kappaB, and inhibited IL-1beta-induced DNA binding of NF-kappaB. Finally, in vivo, fasudil ameliorated arthritis in rats with AIA, without any adverse effects. CONCLUSION:
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Authors | Hiroshi Okamoto, Taku Yoshio, Hirotaka Kaneko, Hisashi Yamanaka |
Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 62
Issue 1
Pg. 82-92
(Jan 2010)
ISSN: 0004-3591 [Print] United States |
PMID | 20039418
(Publication Type: Journal Article)
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Chemical References |
- Cell Adhesion Molecules
- Drug Combinations
- Interleukin-1beta
- NF-kappa B
- Protein Kinase Inhibitors
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
- fasudil
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Topics |
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
(analogs & derivatives, pharmacology)
- Animals
- Arthritis, Experimental
(drug therapy, metabolism, pathology)
- Arthritis, Rheumatoid
(drug therapy, metabolism, pathology)
- Cell Adhesion
(drug effects)
- Cell Adhesion Molecules
(metabolism)
- Cells, Cultured
- Drug Combinations
- Endothelium, Vascular
(drug effects, metabolism, pathology)
- Female
- Genes, Reporter
(drug effects)
- Humans
- Interleukin-1beta
(pharmacology)
- NF-kappa B
(genetics, metabolism)
- Neutrophils
(drug effects, physiology)
- Protein Kinase Inhibitors
(pharmacology)
- Rats
- Rats, Inbred Lew
- Signal Transduction
(drug effects)
- Synovial Membrane
(drug effects, metabolism, pathology)
- Transcriptional Activation
(drug effects)
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