title: Citrullinated fibronectin inhibits apoptosis and promotes the secretion of pro-inflammatory cytokines in fibroblast-like synoviocytes in rheumatoid arthritis.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is characterized by synovial lining hyperplasia, in which there may be an imbalance between the growth and death of fibroblast-like synoviocytes (FLSs). Antibodies against citrullinated proteins are proposed to induce RA. This study aimed to investigate the pathogenic role of citrullinated fibronectin (cFn) in RA.
  
  
  METHODS
  The distribution of fibronectin (Fn) and cFn in synovial tissues from RA and osteoarthritis (OA) patients was examined by immunohistochemical and double immunofluorescence analysis. FLSs were isolated from RA and OA patients and treated with Fn or cFn. Apoptosis was detected by flow cytometry and TUNEL assay. The expression of survivin, caspase-3, cyclin-B1, Bcl-2 and Bax was detected by real-time PCR. The secretion of proinflammatory cytokines was measured by ELISA.
  
  
  RESULTS
  Fn formed extracellular aggregates that were specifically citrullinated in synovial tissues of RA patients, but no Fn deposits were observed in those of OA patients. Fn induced the apoptosis of RA and OA FLSs while cFn inhibited the apoptosis of RA and OA FLSs. Fn significantly increased the expression of caspase-3 and decreased the expression of survivin and cyclin-B1 in FLSs from RA and OA patients. cFn significantly increased the expression of survivin in RA FLSs. Furthermore, cFn increased the secretion of TNF-α and IL-1 by FLSs.
  
  
  CONCLUSIONS
  cFn plays a potential pathophysiologic role in RA by inhibiting apoptosis and increasing proinflammatory cytokine secretion of FLSs.
authors.forename: Lieying
authors.initials: L
authors.lastname: Fan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Rongqing
authors.initials: R
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Zong
authors.forename: Dongyi
authors.initials: D
authors.lastname: He
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ding
authors.forename: Jianwei
authors.initials: J
authors.lastname: Ma
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D005353:Fibronectins / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D006867:Hydrolases / Q000235:genetics; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C107489:BIRC5 protein, human; D056744:Cyclin B1; D016207:Cytokines; D005353:Fibronectins; D018836:Inflammation Mediators; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053245:RANK Ligand; D000077022:Survivin; D051028:bcl-2-Associated X Protein; D002956:Citrulline; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases