title: Heterogeneity of response of rheumatoid synovium cell subsets to interleukin-18 in relation to differential interleukin-18 receptor expression.
abstract: OBJECTIVE
  To examine the differential response of rheumatoid arthritis (RA) synovium cell subsets to interleukin-18 (IL-18), the effect of IL-18 on Th1-cytokine production, and the regulation of IL-18 by IL-18 binding protein (IL-18BP).
  
  
  METHODS
  RA fibroblast-like synoviocytes were stimulated with IL-1 beta, IL-12, and IL-18, and levels of IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). Expression of IL-18 receptor alpha and beta chains (IL-18R alpha and IL-18R beta, respectively), interferon-gamma (IFN gamma), and IL-17 messenger RNA (mRNA) by peripheral blood mononuclear cells, by total RA synovium cells containing T cells obtained after collagenase digestion, and by RA fibroblast-like synoviocytes was determined by reverse transcription-polymerase chain reaction. Levels of IFN gamma were measured by ELISA.
  
  
  RESULTS
  IL-1 beta and, less effectively, IL-12 could induce RA fibroblast-like synoviocytes to produce IL-6, but IL-18 failed to have an effect. Although IL-18R alpha mRNA was constitutively expressed by RA fibroblast-like synoviocytes, IL-18R beta could not be detected, either with or without stimulation with IL-1 or IL-12. Total RA synovium cells containing T cells showed a strong expression of both IL-18R alpha and IL-18R beta mRNA, and only IL-18R beta was up-regulated by IL-12. The combination of IL-12 and IL-18 synergistically up-regulated IFN gamma mRNA expression by total RA synovium cells containing T cells, but down-regulated that of IL-17. IL-12-induced IFN gamma production by total RA synovium cells containing T cells was increased by additional IL-18 and decreased by IL-18BP.
  
  
  CONCLUSIONS
  These results indicate that IL-18 plays an important role in RA inflammation and joint destruction via T cells and macrophages, but it does not have a direct effect on fibroblast-like synoviocytes. IL-18BP may be a tool for RA therapy because of its ability to neutralize endogenous IL-18.
authors.affiliation: Hospital Edouard Herriot, Lyon, France.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawashima
authors.forename: Pierre
authors.initials: P
authors.lastname: Miossec
mesh_terms: D001172:Arthritis, Rheumatoid; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007369:Interferon Inducers / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics; D053724:Receptors, Interleukin-18; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000145:classification / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D006023:Glycoproteins; C508572:IL18R1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D007369:Interferon Inducers; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; C118370:interleukin-18 binding protein