title: Thymidine phosphorylase regulates the expression of CXCL10 in rheumatoid arthritis fibroblast-like synoviocytes.
abstract: OBJECTIVE
  Thymidine phosphorylase (TP) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) is induced by tumor necrosis factor α (TNFα) and other cytokines that have been reported to be major inflammation mediators in RA. We previously demonstrated that TP plays an important role in angiogenesis and tumor growth, invasion, and metastasis. The aim of this study was to investigate whether the role of TP in the pathogenesis of RA is similar to its role in tumors.
  
  
  METHODS
  In FLS obtained from 2 patients with RA, the expression of TP, interferon-γ (IFNγ)-inducible protein 10 (CXCL10), and other cytokines was measured by quantitative real-time polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assays. Microarray analysis was performed using FLS transfected with TYMP complementary DNA and treated with a TP inhibitor.
  
  
  RESULTS
  The expression of TP in FLS was up-regulated by TNFα, interleukin-1β (IL-1β), IL-17, IFNγ, and lipopolysaccharide. Microarray analysis of FLS overexpressing TP identified CXCL10 as a thymidine phosphorylase-related gene. The expression of CXCL10 was induced by TNFα, and this induction was suppressed by TYMP small interfering RNA and TP inhibitor. Furthermore, the combination of TNFα and IFNγ synergistically augmented the expression of TP and CXCL10. TP-induced CXCL10 expression was suppressed by the antioxidant EUK-8. In the synovial tissue of patients with RA, TP levels were significantly correlated with CXCL10 expression.
  
  
  CONCLUSIONS
  The combination of TNFα and IFNγ strongly induced the expression of thymidine phosphorylase in RA FLS. The induction of thymidine phosphorylase enhanced the expression of CXCL10, which may contribute to the Th1 phenotype and bone destruction observed in RA.
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Sho
authors.initials: S
authors.lastname: Tabata
authors.forename: Jun
authors.initials: J
authors.lastname: Kishi
authors.forename: Takuya
authors.initials: T
authors.lastname: Kuramoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mitsuhashi
authors.forename: Atsuro
authors.initials: A
authors.lastname: Saijo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawano
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Goto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Aono
authors.forename: Masaki
authors.initials: M
authors.lastname: Hanibuchi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Horikawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Akiyama
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D054357:Chemokine CXCL10; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013939:Thymidine Phosphorylase