title: Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis.
abstract: OBJECTIVE
  In rheumatoid arthritis (RA), synovial fibroblasts proliferate excessively, eventually eroding bone and cartilage. The aim of this study was to examine the mechanisms through which CD4 T cells, the dominant lymphocyte population in patients with rheumatoid synovitis, regulate synoviocyte proliferation.
  
  
  METHODS
  Fibroblast-like synoviocyte (FLS) lines were established from rheumatoid synovium. CD4 T cells from patients with RA and age-matched control subjects were cultured on FLS monolayers. FLS proliferation was quantified by cytometry, using carboxyfluorescein succinimidyl ester staining or microscopic enumeration of PKH26-stained FLS. Surface expression of the fractalkine (FKN) receptor CX(3)CR1 was monitored by fluorescence-activated cell sorting. The induction of CX(3)CR1 and its ligand FKN in FLS was quantified by real-time polymerase chain reaction.
  
  
  RESULTS
  The proliferation of FLS was significantly increased in the presence of CD4 T cells from patients with RA compared with control T cells. CD4+,CD28- T cells were particularly effective in supporting FLS growth, inducing a 25-fold expansion compared with a 5-fold expansion induced by CD4+,CD28+ T cells. The growth-promoting activity of CD4+,CD28- T cells was mediated through CX(3)CR1, a chemokine receptor expressed on both T cells and FLS. Anti-CX(3)CR1 antibodies inhibited T cell production of tumor necrosis factor alpha (TNFalpha) and suppressed FLS proliferation. TNFalpha amplified the expansion of FLS by enhancing their expression of CX(3)CR1 and FKN.
  
  
  CONCLUSIONS
  FKN-CX(3)CR1 receptor-ligand interactions regulate FLS growth and FLS-dependent T cell function. FLS stimulate autocrine growth by releasing FKN and triggering the activity of their own CX(3)CR1. This growth-promotion loop is amplified by TNFalpha produced by CX(3)CR1-expressing T cells upon stimulation by FKN-expressing FLS. These data assign a critical role to FKN and its receptor in fibroblast proliferation and pannus formation in RA.
authors: Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Hirokazu
authors: H
authors: Sawai
authors: Yong W
authors: YW
authors: Park
authors: Xiaowen
authors: X
authors: He
authors: Jörg J
authors: JJ
authors: Goronzy
authors: Cornelia M
authors: CM
authors: Weyand
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000073883:CX3C Chemokine Receptor 1; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D054428:Chemokine CX3CL1 / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha