oxazolone and Arthritis--Rheumatoid

Rheumatoid arthritis (RA) is an aggressive inflammatory disease in which cytokines/chemokines are thought to recruit leukocytes and induce angiogenesis. The aim of this study is to investigate the effect of flavonol-rich residual layer of hexane fraction from Rhus verniciflua Stokes (RVHxR) and its major compound fisetin on inflammatory cytokine/chemokine production and angiogenic factor in IL-1beta-stimulated RA fibroblast-like synovial cells (FLS) and inflammatory in vivo models. Flavonol-rich RVHxR and its major compound fisetin significantly inhibited IL-1beta-induced FLS proliferation in a dose-dependent manner. Flavonol-rich RVHxR and fisetin significantly decreased IL-1beta-induced inflammatory cytokines (TNF-alpha, interleukin (IL)-6)/chemokines (IL-8, monocyte chemoattractant protein (MCP)-1), and vascular endothelial growth factor (VEGF) of RA FLS. Flavonol-rich RVHxR dose dependently diminished the phophorylation of extracellular signal regulated kinase (ERK) and phospho-Jun NH((2))-terminal kinase (JNK), and its down regulation induced by RVHxR at nontoxic concentrations, while activated the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS. The p38 specific inhibitor SB203580 cotreatment with RVHxR effectively increased the expression of VEGF and blocked the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS, confirming a critical role of p38 MAPK pathway in angiogenesis inhibition. In experimental inflammation-related models, flavonol-rich RVHxR and fisetin have shown significant anti-inflammatory activities on vascular permeability, leukocyte migration and cellular immunity. Also, flavonol-rich RVHxR and fisetin treatments significantly reduced the incidence and severity of collagen-induced arthritis model. These results suggest that RVHxR and its major compound fisetin have shown potent suppressive effects on some inflammatory cytokines/chemokines and angiogenic factor in IL-1beta-stimulated RA FLS and inflammatory in vivo models. We believe that flavonol-rich RVHxR is a potential therapeutic agent in the treatment of inflammatory and angiogenesis related diseases.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cell Movement; Cell Proliferation; Collagen Type II; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Fibroblasts; Flavonoids; Flavonols; Humans; Hypersensitivity, Delayed; Imidazoles; Interleukin-1beta; Mice; Mice, Inbred DBA; Neovascularization, Pathologic; Oxazolone; Protein Kinases; Pyridines; Rats; Rats, Sprague-Dawley; Rhus; Synovial Membrane; Vascular Endothelial Growth Factor A

Levamisole, but not D-penicillamine, inhibited the oxazolone delayed hypersensitivity in rats. It was more effective when given locally to the ear (the tissue being challenged with oxazolone) or when injected intraperitoneally 24 h previously. Rats bred for resistance to the dextran anaphylactoid reaction exhibit contact sensitivity to oxazolone even better than rats which respond to clinical dextran.

Topics: Anaphylaxis; Animals; Arthritis, Rheumatoid; Dermatitis, Contact; Female; Levamisole; Oxazoles; Oxazolone; Penicillamine; Rats; Rats, Inbred Strains