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.

Abstract

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.

• Authors: Jae-Dong Lee, Jeong-Eun Huh, GeumSeon Jeon, Ha-Ru Yang, Hyun-Su Woo, Do-Young Choi, Dong-Suk Park
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 9 Issue 3 Pg. 268-76 (Mar 2009) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 19111632 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Anti-Inflammatory Agents, Non-Steroidal
• Collagen Type II
• Cytokines
• Enzyme Inhibitors
• Flavonoids
• Flavonols
• Imidazoles
• Interleukin-1beta
• Pyridines
• Vascular Endothelial Growth Factor A
• Oxazolone
• Protein Kinases
• fisetin
• SB 203580

Topics

• Angiogenesis Inhibitors (isolation & purification, therapeutic use)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (isolation & purification, therapeutic use)
• Arthritis, Rheumatoid (drug therapy, immunology)
• Cell Movement (drug effects, immunology)
• Cell Proliferation (drug effects)
• Collagen Type II (pharmacology)
• Cytokines (antagonists & inhibitors)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (drug effects, immunology)
• Flavonoids (isolation & purification, pharmacology)
• Flavonols
• Humans
• Hypersensitivity, Delayed (drug therapy, immunology)
• Imidazoles (pharmacology)
• Interleukin-1beta (pharmacology)
• Mice
• Mice, Inbred DBA
• Neovascularization, Pathologic (drug therapy, immunology)
• Oxazolone (pharmacology)
• Protein Kinases (drug effects, metabolism)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rhus (chemistry)
• Synovial Membrane (drug effects, immunology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)