Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models

• Published in: International immunopharmacology Vol. 9; no. 3; pp. 268 - 276
• Main Authors: Lee, Jae-Dong, Huh, Jeong-Eun, Jeon, GeumSeon, Yang, Ha-Ru, Woo, Hyun-Su, Choi, Do-Young, Park, Dong-Suk
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2009
• Subjects: Angiogenesis; Angiogenesis Inhibitors - isolation & purification; Angiogenesis Inhibitors - therapeutic use; Animals; Anti-Inflammatory Agents, Non-Steroidal - isolation & purification; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Cell Movement - drug effects; Cell Movement - immunology; Cell Proliferation - drug effects; Collagen Type II - pharmacology; Cytokines - antagonists & inhibitors; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Fibroblasts - drug effects; Fibroblasts - immunology; Fisetin; Flavonoids - isolation & purification; Flavonoids - pharmacology; Flavonol-rich RVHxR; Humans; Hypersensitivity, Delayed - drug therapy; Hypersensitivity, Delayed - immunology; Imidazoles - pharmacology; Inflammation; Interleukin-1beta - pharmacology; Mice; Mice, Inbred DBA; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - immunology; Oxazolone - pharmacology; Protein Kinases - drug effects; Protein Kinases - metabolism; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Rhus; Rhus - chemistry; Rhus verniciflua Stokes; Synovial Membrane - drug effects; Synovial Membrane - immunology; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Rhus verniciflua Stokes; Fisetin; Angiogenesis; Flavonol-rich RVHxR; Inflammation
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2008.11.005

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-1β-stimulated RA fibroblast-like synovial cells (FLS) and inflammatory in vivo models. Flavonol-rich RVHxR and its major compound fisetin significantly inhibited IL-1β-induced FLS proliferation in a dose-dependent manner. Flavonol-rich RVHxR and fisetin significantly decreased IL-1β-induced inflammatory cytokines (TNF-α, 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-1β-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-1β-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-1β-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.