title: Association of interleukin-18 expression with enhanced levels of both interleukin-1beta and tumor necrosis factor alpha in knee synovial tissue of patients with rheumatoid arthritis.
abstract: OBJECTIVE
  To examine the expression patterns of interkeukin-18 (IL-18) in synovial biopsy tissue of patients with rheumatoid arthritis (RA), and to determine whether expression of this primary cytokine is related to the expression of other cytokines and adhesion molecules and related to the degree of joint inflammation.
  
  
  METHODS
  Biopsy specimens of knee synovial tissue either without synovitis (n = 6) or with moderate or severe synovitis (n = 11 and n = 12, respectively) were obtained from 29 patients with active RA. Paraffin-embedded, snap-frozen sections were used for immunohistochemical detection of IL-18, tumor necrosis factor alpha (TNFalpha), IL-1beta, IL-12, and IL-17. Furthermore, adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin, and cell markers CD3, CD14, and CD68 were stained.
  
  
  RESULTS
  IL-18 staining was detectable in 80% of the RA patients, in both the lining and sublining of the knee synovial tissue. IL-18 expression in the synovial tissue was strongly correlated with the expression of IL-1beta (in the sublining r = 0.72, in the lining r = 0.71; both P < 0.0001) and TNFalpha (in the sublining r = 0.59, P < 0.0007, and in the lining r = 0.68, P < 0.0001). In addition, IL-18 expression in the sublining correlated with macrophage infiltration (r = 0.64, P < 0.0007) and microscopic inflammation scores (r = 0.78, P < 0.0001), and with the acute-phase reaction as measured by the erythrocyte sedimentation rate (r = 0.61, P < 0.0004). Interestingly, RA synovial tissue that coexpressed IL-18 and IL-12 demonstrated enhanced levels of the Th1-associated cytokine IL-17.
  
  
  CONCLUSIONS
  Our results show that expression of IL-18 is associated with that of IL-1beta and TNFalpha and with local inflammation in the synovial tissue of patients with RA. In addition, synovial IL-18 expression correlates with the acute-phase response. These data indicate that IL-18 is a primary proinflammatory cytokine in RA that drives the local production of IL-1beta and TNFalpha.
authors.affiliation: Rheumatology Research Laboratory, University Medical Center Nijmegen, Nijmegen, The Netherlands. l.joosten@reum.azn.nl
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Timothy R D
authors.initials: TR
authors.lastname: Radstake
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
authors.forename: Liduine A M
authors.initials: LA
authors.lastname: van den Bersselaar
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000209:Acute-Phase Proteins / Q000276:immunology; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D001706:Biopsy; D016207:Cytokines / Q000378:metabolism*; D019040:E-Selectin / Q000378:metabolism; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D007719:Knee Joint / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D000209:Acute-Phase Proteins; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016207:Cytokines; D019040:E-Selectin; D018799:Intercellular Adhesion Molecule-1; D007375:Interleukin-1; D018664:Interleukin-12; D020381:Interleukin-17; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C067980:CD68 antigen, human; D000097382:CD68 Molecule