title: Increased expression of Fcgamma receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor alpha and matrix metalloproteinase.
abstract: OBJECTIVE
  To evaluate Fcgamma receptor (FcgammaR) expression on synovial macrophages from rheumatoid arthritis (RA) patients and to determine whether this expression correlates with the production of the proinflammatory cytokines tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), IL-12, and matrix metalloproteinase 1 (MMP-1). We also sought to determine whether mature macrophages from RA patients express aberrant levels of FcgammaRI, FcgammaRII, and FcgammaRIII, and to determine the production of inflammatory mediators after immune complex (IC) stimulation.
  
  
  METHODS
  Immunohistochemistry was performed on cryostat sections of synovial biopsy specimens obtained from 27 RA patients and 5 controls. FcgammaR I, II, and III were detected, as well as the proinflammatory mediators IL-1, TNFalpha, IL-12, and MMP-1. Monocytes were isolated from the blood of 10 RA patients and 10 healthy controls and cultured for 7 days with macrophage colony-stimulating factor to obtain macrophages. Using fluorescence-activated cell sorting, the expression of FcgammaRI, FcgammaRII, and FcgammaRIII was determined. On day 7, macrophages were stimulated with heat-aggregated gamma globulins (HAGGs) for 24 hours. Production of cytokines was measured using enzyme-linked immunosorbent assay, and production of gelatinases/collagenases was measured by degradation of fluorescent gelatin.
  
  
  RESULTS
  Immunohistochemistry showed higher FcgammaRII and FcgammaRIII expression in RA synovium than in controls. FcgammaRII and FcgammaRIII, but not FcgammaRI, were highly correlated with the number of synovial macrophages. Consistent with this, TNFalpha expression correlated positively with FcgammaRIII expression. Moreover, MMP-1 expression strongly correlated with FcgammaR I, II, and III expression. Mature macrophages from RA patients showed significantly enhanced expression of FcgammaRII and FcgammaRIII compared with controls. Twenty-four hours after stimulation of RA macrophages with HAGGs, significantly higher production of TNFalpha and gelatinase/collagenase was measured.
  
  
  CONCLUSIONS
  RA synovium and mature RA macrophages express significantly elevated levels of FcgammaRII and FcgammaRIII, resulting in much higher production of TNFalpha and gelatinase/collagenase after IC stimulation. These data suggest that disturbed expression of FcgammaR on mature synovial macrophages is involved in the pathology of RA.
authors.affiliation: University Medical Center, Nijmegen, The Netherlands.
authors.forename: Arjen B
authors.initials: AB
authors.lastname: Blom
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: Astrid E M
authors.initials: AE
authors.lastname: Holthuysen
authors.forename: Annet W
authors.initials: AW
authors.lastname: Slöetjes
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Pesman
authors.forename: Fred G J
authors.initials: FG
authors.lastname: Sweep
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
authors.forename: L A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007375:Interleukin-1 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D007375:Interleukin-1; D012333:RNA, Messenger; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D020781:Matrix Metalloproteinase 1