Soluble Fas ligand inhibits angiogenesis in rheumatoid arthritis

• Published in: Arthritis research & therapy 2007-01, Vol.9 (2), p.R42-R42, Article R42
• Main Authors: Kim, Wan-Uk, Kwok, Seung-Ki, Hong, Kyung-Hee, Yoo, Seung-Ah, Kong, Jin-Sun, Choe, Jongseon, Cho, Chul-Soo
• Format: Article
• Language: English
• Subjects: Apoptosis - physiology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Blotting, Western; Cell Movement - physiology; Cells, Cultured; Development and progression; Endothelial Cells - metabolism; Endothelial Cells - pathology; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases - metabolism; Fas Ligand Protein - metabolism; Female; Humans; Male; Middle Aged; Neovascularization; Neovascularization, Pathologic - metabolism; Phosphorylation; Physiological aspects; Proto-Oncogene Proteins c-akt - metabolism; Rheumatoid arthritis; Synovial Fluid - chemistry; Synovial Fluid - metabolism; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1478-6354; 1478-6362; 1478-6354
• DOI: 10.1186/ar2181

The characteristics of rheumatoid arthritis (RA) pathology include the infiltration of inflammatory leukocytes, the proliferation of synovial cells, and the presence of extensive angiogenesis, referred to as rheumatoid pannus. Fas ligand is critical to the homeostatic regulation of the immune response, but its role in the angiogenic process of RA remains to be defined. In this study, we investigated whether soluble Fas ligand (sFasL) induces synoviocyte apoptosis and regulates angiogenesis of endothelial cells in RA. The levels of sFasL were elevated in the synovial fluids of RA patients when compared to those of osteoarthritis (OA) patients, and they correlated inversely with vascular endothelial growth factor165 (VEGF165) concentrations. sFasL, ranging from 10 to 100 ng/ml, induced the apoptosis of RA fibroblast-like synoviocytes (FLS) in vitro, and thereby decreased VEGF165 production. In addition, sFasL inhibited VEGF165-induced migration and chemotaxis of endothelial cells to basal levels in a manner independent of the Fas-mediated cell death. sFasL dose-dependently suppressed the VEGF165-stimulated increase in pAkt expression in endothelial cells, which might be associated with its anti-migratory effect on endothelial cells. Moreover, sFasL strongly inhibited neovascularization in the Matrigel plug in vivo. Our data suggest that sFasL shows anti-angiogenic activity within RA joints not only by inducing apoptosis of VEGF165-producing cells but also by blocking VEGF165-induced migration of endothelial cells, independent of Fas-mediated apoptosis.