Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis

Arthritis Rheum. 2003 Jun;48(6):1521-9. doi: 10.1002/art.11143.


Objective: To investigate whether interleukin-6 (IL-6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA).

Methods: Serum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL-6, IL-1beta, and/or tumor necrosis factor alpha (TNFalpha) was measured. The inhibitory effect of anti-IL-6R mAb, recombinant IL-1 receptor antagonist (IL-1Ra), and anti-TNFalpha mAb on VEGF production was also examined.

Results: Serum VEGF levels in RA patients before anti-IL-6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with anti-IL-6R mAb normalized serum VEGF levels. In the in vitro study, IL-6 and IL-1beta each induced a slight amount of VEGF production in synovial cells, but TNFalpha did not. Although VEGF-inducing activity of these cytokines was not remarkable when they were added alone, IL-6 acted synergistically with IL-1beta or TNFalpha to induce VEGF production. There was no synergistic effect between IL-1beta and TNFalpha. In the presence of all of these cytokines, anti-IL-6R mAb eliminated the synergistic effect of IL-6, IL-1beta, and TNFalpha, while IL-1Ra or anti-TNFalpha mAb did not.

Conclusion: Anti-IL-6R mAb therapy reduced VEGF production in RA. IL-6 is the pivotal cytokine that induces VEGF production in synergy with IL-1beta or TNFalpha, and this may be the mechanism by which IL-6 blockade effectively suppresses VEGF production in synovial fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / therapeutic use*
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / drug therapy*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Endothelial Growth Factors / blood*
  • Endothelial Growth Factors / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Intercellular Signaling Peptides and Proteins / blood*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Interleukin-1 / pharmacology
  • Interleukin-6 / immunology
  • Interleukin-6 / pharmacology
  • Joints / pathology
  • Joints / physiopathology
  • Lymphokines / blood*
  • Lymphokines / genetics
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-6 / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Time Factors
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Antibodies, Monoclonal
  • Drug Combinations
  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-1
  • Interleukin-6
  • Lymphokines
  • RNA, Messenger
  • Receptors, Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors