title: Expression of Toll-like receptors and their signaling pathways in rheumatoid synovitis.
abstract: OBJECTIVE
  Toll-like receptors (TLR) recognizing endogenous and exogenous danger signals could play a role in rheumatoid arthritis (RA). Our aim was to describe the presence, localization, and extent of expression of TLR and their adapters.
  
  
  METHODS
  TLR 1, 2, 3, 4, 5, 6, and 9 receptors, and myeloid differentiation primary response protein 88, Toll/interleukin receptor (TIR) domain-containing adapter protein MyD88 adapter-like, and TIR domain-containing adapter-inducing interferon/TIR-containing adapter molecule-1 adapters were analyzed in RA (n = 10) and osteoarthritis (OA; n = 5) samples using real-time polymerase chain reaction (PCR). Their colocalization with cellular markers CD68, CD15, CD3, CD4, CD8, CD20, dendritic cell lysosomal-associated membrane protein (DC-LAMP), CD123, and 5B5 was analyzed in double immunofluorescence staining.
  
  
  RESULTS
  In RA, ß-actin standardized messenger RNA of TLR 2, 3, and 9 (p < 0.001) were particularly high. TLR 5 and 6 were also elevated (p < 0.05), but TLR 1 and 4 and adapters did not differ between RA and OA. In double-staining, TLR and adapters were strongly labeled in myeloid and plasmacytoid dendritic cells (DC), moderately in CD68+ type A lining cells/macrophages, and weakly to moderately in 5B5+ type B lining cells/fibroblasts. CD3+/CD4+ and CD3+/CD8+ T cells and CD20+ B cells in perivenular areas and in lymphoid follicles were moderately TLR- and weakly adapter-positive. In OA, TLR and adapters were weakly immunolabeled in vascular, lining, and inflammatory cells.
  
  
  CONCLUSIONS
  RA synovium showed abundant expression of TLR. RA synovitis tissue seems to be responsive to TLR ligands. DC, type A cells/macrophages, and type B cells/fibroblasts are, in that order from highest to lowest, equipped with TLR, suggesting a hierarchical responsiveness. In RA, danger-associated molecular patterns to TLR interactions may particularly drive DC to autoinflammatory and autoimmune cascades/synovitis.
authors.affiliation: Department of Orthopaedic Surgery, Yamagata University School of Medicine, 2-2-2 Iida Nishi, Yamagata, Japan. ytamaki@med.id.yamagata-u.ac.jp
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Tamaki
authors.forename: Yuya
authors.initials: Y
authors.lastname: Takakubo
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hirayama
authors.forename: Yrjö T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Yamakawa
authors.forename: Michiaki
authors.initials: M
authors.lastname: Takagi
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013585:Synovitis / Q000235:genetics* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D017931:DNA Primers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; C470409:TICAM1 protein, human; C434984:TIRAP protein, human; D051193:Toll-Like Receptors