title: Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: a link between angiogenesis and inflammation.
abstract: OBJECTIVE
  To investigate the direct effects of placenta growth factor (PlGF) and its specific receptor, flt-1, which are known to mediate angiogenesis, on the inflammatory process of rheumatoid arthritis (RA).
  
  
  METHODS
  Expression of PlGF and flt-1 in the synovial tissue of RA patients was examined using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the concentrations of PlGF, tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) in culture supernatants of either mononuclear cells or synoviocytes. The flt-1 expression level in mononuclear cells was analyzed by flow cytometry. Experimental arthritis was induced in mice either by immunization with type II collagen (CII) or by injection of anti-CII antibody.
  
  
  RESULTS
  PlGF was highly expressed in the synovium of RA patients, and its primary source was fibroblast-like synoviocytes (FLS). When stimulated with IL-1beta, FLS from RA patients produced higher amounts of PlGF than did FLS from patients with osteoarthritis. Exogenous PlGF specifically increased the production of TNFalpha and IL-6 in mononuclear cells from RA patients (but not those from healthy controls) via a calcineurin-dependent pathway. The response to PlGF was associated with increased expression of flt-1 on RA monocytes, which could be induced by IL-1beta and TNFalpha. A novel anti-flt-1 hexapeptide, GNQWFI, abrogated the PlGF-induced increase in TNFalpha and IL-6 production, and also suppressed CII-induced arthritis and serum IL-6 concentrations in mice. Moreover, genetic ablation of PlGF prevented the development of anti-CII antibody-induced arthritis in mice.
  
  
  CONCLUSIONS
  Our data suggest that enhanced expression of PlGF and flt-1 may contribute to rheumatoid inflammation by triggering production of proinflammatory cytokines. The use of the novel anti-flt-1 peptide, GNQWFI, may be an effective strategy for the treatment of RA.
authors.affiliation: Catholic University of Korea, Seoul, Korea.
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yoo
authors.forename: Hyung-Ju
authors.initials: HJ
authors.lastname: Yoon
authors.forename: Hyun-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Chi-Bom
authors.initials: CB
authors.lastname: Chae
authors.forename: Sandro
authors.initials: S
authors.lastname: De Falco
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D013583:Synovial Membrane / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D009842:Oligopeptides; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D014409:Tumor Necrosis Factor-alpha; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1