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


CONCLUSIONS
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.
Nakahara
Hideko
H
Department of Medical Science I, School of Health and Sport Sciences, Osaka University, Osaka, Japan.
Song
Jian
J
Sugimoto
Masamichi
M
Hagihara
Keisuke
K
Kishimoto
Tadamitsu
T
Yoshizaki
Kazuyuki
K
Nishimoto
Norihiro
N
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000097:blood* / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology; D007596:Joints / Q000473:pathology / Q000503:physiopathology; D008222:Lymphokines / Q000097:blood* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008222:Lymphokines; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors