title: Tacrolimus down-regulates chemokine expressions on rheumatoid synovial fibroblasts: screening by a DNA microarray.
abstract: OBJECTIVE
  Although the effects of tacrolimus on T cells are well-known, direct effects on rheumatoid synovial fibroblasts (RSF) remain unclear. We studied the effects of tacrolimus on RSF by a DNA microarray analysis.
  
  
  METHODS
  Tacrolimus and interleukin (IL)-1β were added to cultured RSF. Total RNA was prepared from the cells and the gene expression profile was analyzed by a DNA microarray screening system. mRNA expressions influenced by tacrolimus in the screening system were confirmed by real-time PCR. The effects of tacrolimus on nuclear translocation of nuclear factor-κB (NF-κB) were also examined.
  
  
  RESULTS
  The mRNA expressions of CCL3, CCL4, and CXCL8 were up-regulated by IL-1β and down-regulated by tacrolimus. The levels of these IL-1β-induced chemokines in culture supernatant were decreased by a therapeutic concentration of tacrolimus. Tumor necrosis factor-α as well as IL-1β induced these chemokines, while tacrolimus inhibited their production and mRNA expression. Chemotaxis of polymorphonuclear cells in response to IL-1β was also inhibited by tacrolimus. Nuclear translocation of p50 and p65 NF-κB in response to IL-1β was decreased by tacrolimus.
  
  
  CONCLUSIONS
  IL-1β-induced chemokine expressions were down-regulated by tacrolimus, suggesting that tacrolimus exerts its anti-inflammatory effect partly through inhibiting chemokine production by RSF.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Kitahara
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kusunoki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kawai
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics*; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D018925:Chemokines; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D016559:Tacrolimus