title: Engagement of toll-like receptor 3 induces vascular endothelial growth factor and interleukin-8 in human rheumatoid synovial fibroblasts.
abstract: OBJECTIVE
  Angiogenesis, which is a critical step in the initiation and progression of rheumatoid arthritis (RA), involves pro-angiogenic factors, including interleukin (IL)-8 and vascular endothelial growth factor (VEGF). We investigated the role of Toll-like receptor 3 (TLR3) in the regulation of pro-angiogenic factors in RA fibroblast-like synoviocytes (FLS).
  
  
  METHODS
  FLS were isolated from RA synovial tissues and stimulated with the TLR3 ligand, poly (I:C). The levels of VEGF and IL-8 in the culture supernatants were measured using enzyme-linked immunosorbent assays, and the mRNA levels were assessed by semiquantitative reverse transcription-polymerase chain reaction. The expression patterns of VEGF and IL-8 in the RA synovium and osteoarthritis (OA) synovium were compared using immunohistochemistry.
  
  
  RESULTS
  The expression levels of TLR3, VEGF, and IL-8 were significantly higher in the RA synovium than in the OA synovium. VEGF and IL-8 production were increased in the culture supernatants of RA FLS stimulated with poly (I:C), and the genes for these proteins were up-regulated at the transcriptional level after poly (I:C) treatment. Treatment with inhibitors of nuclear factor-kappaB (NF-κB), i.e., pyrrolidine dithiocarbamate and parthenolide, abrogated the stimulatory effect of poly (I:C) on the production of VEGF and IL-8 in RA FLS.
  
  
  CONCLUSIONS
  Our results suggest that the activation of TLR3 in RA FLS promotes the production of proangiogenic factors, in a process that is mediated by the NF-κB signaling pathway. Therefore, targeting the TLR3 pathway may be a promising approach to preventing pathologic angiogenesis in RA.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Moon
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Hye-Jwa
authors.initials: HJ
authors.lastname: Oh
authors.forename: Seon-Yeong
authors.initials: SY
authors.lastname: Lee
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Kyung-Su
authors.initials: KS
authors.lastname: Park
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000209:etiology; D012333:RNA, Messenger / Q000032:analysis; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000032:analysis / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D042461:Vascular Endothelial Growth Factor A