Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor ? and interleukin-1 in rheumatoid arthritis

Open Access
Publisher Website
Google Scholar
Abstract
Objective To investigate the regulation of expression of the angiogenic cytokine vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA), in order to determine whether new blood vessel formation could be a potential therapeutic target in RA. Methods Dissociated RA synovial membrane cells were cultured in the presence of cytokine inhibitors, or under hypoxic conditions. Serum VEGF levels were serially measured in RA patients enrolled in clinical trials of anti‐tumor necrosis factor α (anti‐TNFα) monoclonal antibody treatment. Results Combined neutralization of TNFα and interleukin‐1 (IL‐1) in RA synovial membrane cultures reduced VEGF release by 45% (P < 0.05 versus control), although blockade of either TNFα or IL‐1 activities alone resulted in only small inhibitory effects. In addition, release of VEGF from RA synovial membrane cells was selectively up‐regulated by hypoxia. Serum VEGF levels were significantly elevated in RA patients relative to control subjects, and correlated with disease activity. Treatment of RA patients with anti‐TNFα significantly decreased serum VEGF, and this effect was enhanced by cotreatment with methotrexate. Conclusion Inhibition of TNFα and IL‐1 activity in vivo could reduce the drive to new blood vessel formation, and hence pannus mass, adding to other therapeutic effects of anti‐TNFα therapy in RA.