title: Potentiation of glucocorticoid receptor (GR)-mediated signaling by the immunosuppressant tacrolimus in rheumatoid synoviocytes.
abstract: OBJECTIVE
  The immunosuppressant tacrolimus is known to enhance many aspects of glucocorticoid. In this study, we investigated the effects of tacrolimus on glucocorticoid receptor (GR) signaling using rheumatoid fibroblast-like synoviocytes (RA-FLS).
  
  
  METHODS
  The nuclear translocation of GR was analyzed by immunocytochemistry. The DNA binding activity of p65 was assayed by a functional ELISA kit using nuclear extracts. GR-associated FK506-binding protein-51 (FKBP-51) was analyzed by Western blotting following immunoprecipitation of glucocorticoid receptor (GR) complexes.
  
  
  RESULTS
  High concentrations (10-7M) of Dexamethasone (Dex) induced GR translocation to the nucleus in RA-FLS. However, the nuclear GR translocation did not occur with low concentrations of Dex (10-9M). Tacrolimus treatment of RA-FLS results in potentiation of GR translocation to the nucleus even in the presence of a low concentration of Dex (10-9M). GR-associated FKBP-51 decreased after tacrolimus treatment. Furthermore, tacrolimus also decreased the IL-1Beta-induced DNA binding activity of p65, a subunit of NF-KappaB, in the presence of 10-9 M of Dex.
  
  
  CONCLUSIONS
  These data suggest that tacrolimus exerts anti-inflammatory properties by potentiating the GR signaling through the GR-immunosuppressant-binding proteins (immunophilins) interaction and its nuclear transport in rheumatoid synovium.
authors.affiliation: Clinical Research Center and Department of Rheumatology, NHO Nagasaki Medical Center, Nagasaki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Torigoshi
authors.forename: S
authors.initials: S
authors.lastname: Motokawa
authors.forename: T
authors.initials: T
authors.lastname: Miyashita
authors.forename: Y
authors.initials: Y
authors.lastname: Maeda
authors.forename: T
authors.initials: T
authors.lastname: Koga
authors.forename: M
authors.initials: M
authors.lastname: Nakamura
authors.forename: A
authors.initials: A
authors.lastname: Komori
authors.forename: Y
authors.initials: Y
authors.lastname: Aiba
authors.forename: T
authors.initials: T
authors.lastname: Uemura
authors.forename: H
authors.initials: H
authors.lastname: Yatsuhashi
authors.forename: H
authors.initials: H
authors.lastname: Ishibashi
authors.forename: K
authors.initials: K
authors.lastname: Eguchi
authors.forename: H
authors.initials: H
authors.lastname: Shindo
authors.forename: K
authors.initials: K
authors.lastname: Migita
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D011965:Receptors, Glucocorticoid; D016559:Tacrolimus