Vascular Endothelial Growth Factor Stimulates Productions of Tumor Necrosis Factor-alpha and Interleukin-6 from Mononuclear Cells and Synoviocytes of Rheumatoid Arthritis Patients / 대한류마티스학회지

ABSTRACT

OBJECTIVE: Vascular endothelial growth factor (VEGF), an angiogenic factor, has been suggested to play a critical role in the pathogenesis of rheumatoid arthritis (RA). In this study, we investigated whether VEGF would directly regulate the activation of mononuclear cells of RA patients. MEHTODS Mononuclear cells and/or synoviocytes of RA patients were cultured in the presence of VEGF, and the levels of TNF-alpha and IL-6 were determined in the culture supernatants by ELISA. The TNF-alpha-or IL-6-producing cells were also assessed by flow cytometry analysis. Blocking experiments were performed by adding anti-VEGF receptor (anti-Flt-1) mAb to the cells, stimulated with VEGF. RESULTS: VEGF directly increased the productions of TNF-alpha and IL-6 from peripheral blood mononuclear cells (PBMC) from healthy controls. Treatment of PBMC with anti-VEGF receptor (anti-Flt-1) mAb blocked the VEGF-induced productions of TNF-alpha and IL-6, suggesting that VEGF activates the PBMC via a receptor (Flt-1) coupling event. Synovial fluid mononuclear cells (SFMC) of RA patients showed a greater response to VEGF stimulation than the PBMC of healthy controls. The major cell types responding to VEGF were monocytes and synoviocytes. In addition, dexamethasone completely abrogated VEGF- stimulated productions of TNF-alpha and IL-6 from adherent cells, isolated from SFMC. CONCLUSION: Our data suggest that VEGF may directly activate RA monocytes and synoviocytes to produce TNF-alpha and IL-6.