title: Arginine-rich anti-vascular endothelial growth factor (anti-VEGF) hexapeptide inhibits collagen-induced arthritis and VEGF-stimulated productions of TNF-alpha and IL-6 by human monocytes.
abstract: Vascular endothelial growth factor (VEGF) has been suggested to play a critical role in the pathogenesis of rheumatoid arthritis (RA). We previously identified a novel RRKRRR hexapeptide that blocked the interaction between VEGF and its receptor through the screening of peptide libraries. In this study, we investigated whether anti-VEGF peptide RRKRRR (dRK6) could suppress collagen-induced arthritis (CIA) and regulate the activation of mononuclear cells of RA patients. A s.c. injection of dRK6 resulted in a dose-dependent decrease in the severity and incidence of CIA and suppressed synovial infiltration of inflammatory cells in DBA/1 mice. In these mice, the T cell responses to type II collagen (CII) in lymph node cells and circulating IgG Abs to CII were also dose-dependently inhibited by the peptides. In addition, VEGF directly increased the production of TNF-alpha and IL-6 from human PBMC. Synovial fluid mononuclear cells of RA patients showed a greater response to VEGF stimulation than the PBMC of healthy controls. The major cell types responding to VEGF were monocytes. Moreover, anti-VEGF dRK6 inhibited the VEGF-induced production of TNF-alpha and IL-6 from synovial fluid mononuclear cells of RA patients and decreased serum IL-6 levels in CIA mice. In summary, we observed first that dRK6 suppressed the ongoing paw inflammation in mice and blocked the VEGF-induced production of proinflammatory cytokines. These data suggest that dRK6 may be an effective strategy in the treatment of RA, and could be applied to modulate various chronic VEGF-dependent inflammatory diseases.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Catholic University of Korea, Seoul.
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yoo
authors.forename: Dong-Goo
authors.initials: DG
authors.lastname: Bae
authors.forename: Jae-Woong
authors.initials: JW
authors.lastname: Ryoo
authors.forename: Hae-Rim
authors.initials: HR
authors.lastname: Kim
authors.forename: Gyeong-Sin
authors.initials: GS
authors.lastname: Park
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.forename: Chi-Bom
authors.initials: CB
authors.lastname: Chae
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
mesh_terms: D000818:Animals; D001120:Arginine; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors / Q000276:immunology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
chemical_list: D001120:Arginine; D003094:Collagen; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D009842:Oligopeptides; D040262:Receptors, Vascular Endothelial Growth Factor; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C501225:arginyl-arginyl-lysyl-arginyl-arginyl-arginine; C492739:hexaarginine amide