Tumor necrosis factor-α induces vascular endothelial growth factor-C expression in rheumatoid synoviocytes

Objective. To determine the expression of vascular endothelial growth factor-C (VEGF-C) in the synovial fluid of patients with rheumatoid arthritis (RA) and to investigate the regulation of VEGF-C production by major proinflammatory cytokines in fibroblast-like synoviocytes (FLS). Methods. The concentrations of VEGF-C, tumor necrosis factor-alpha (TNF-alpha), and interleukin 1 beta (IL-1 beta) were measured using an ELISA method in synovial fluids obtained from 20 patients with RA and 20 with osteoarthritis (OA). Primary cultured RA FLS were stimulated with TNF-alpha or IL-1 beta. and the expression levels of VEGF-C mRNA and protein were assessed by quantitative real-time polymerase chain reaction and ELISA. Results. Significantly higher levels of VEGF-C were found in RA synovial fluids compared to OA synovial fluids. VEGF-C levels showed a highly significant correlation with the levels of both TNF-alpha and IL-1 beta in the synovial fluid of patients with RA. TNF-a stimulation significantly increased VEGF-C mRNA and protein expression in RA FLS in a dose-dependent manner. A tendency to increased expression of VEGF-C was also observed after IL-1 beta stimulation in FLS. Conclusion. Overexpression of VEGF-C in FLS by stimulation with TNF-alpha may play an important role in the progression of synovial inflammation and hyperplasia in RA by contributing to local lymphangiogenesis and angiogenesis.