Document Detail

Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis.
MedLine Citation:
PMID:  12794819     Owner:  NLM     Status:  MEDLINE    
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.
Hideko Nakahara; Jian Song; Masamichi Sugimoto; Keisuke Hagihara; Tadamitsu Kishimoto; Kazuyuki Yoshizaki; Norihiro Nishimoto
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  48     ISSN:  0004-3591     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2003 Jun 
Date Detail:
Created Date:  2003-06-09     Completed Date:  2003-07-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1521-9     Citation Subset:  AIM; IM    
Department of Medical Science I, School of Health and Sport Sciences, Osaka University, Osaka, Japan.
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MeSH Terms
Antibodies, Monoclonal / therapeutic use*
Arthritis, Rheumatoid / blood,  drug therapy*
Cells, Cultured
Dose-Response Relationship, Drug
Drug Combinations
Endothelial Growth Factors / blood*,  genetics
Enzyme-Linked Immunosorbent Assay
Fibroblasts / drug effects,  metabolism,  pathology
Intercellular Signaling Peptides and Proteins / blood*,  genetics
Interleukin-1 / pharmacology
Interleukin-6 / immunology,  pharmacology
Joints / pathology,  physiopathology
Lymphokines / blood*,  genetics
RNA, Messenger / metabolism
Receptors, Interleukin-6 / immunology*
Reverse Transcriptase Polymerase Chain Reaction
Synovial Membrane / drug effects,  metabolism,  pathology
Time Factors
Tumor Necrosis Factor-alpha / immunology,  pharmacology
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Drug Combinations; 0/Endothelial Growth Factors; 0/Intercellular Signaling Peptides and Proteins; 0/Interleukin-1; 0/Interleukin-6; 0/Lymphokines; 0/RNA, Messenger; 0/Receptors, Interleukin-6; 0/Tumor Necrosis Factor-alpha; 0/Vascular Endothelial Growth Factor A; 0/Vascular Endothelial Growth Factors
Comment In:
Arthritis Rheum. 2003 Jun;48(6):1471-4   [PMID:  12794810 ]
Arthritis Rheum. 2004 Jun;50(6):2037   [PMID:  15188386 ]

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