Potentiation of glucocorticoid receptor (GR)-mediated signaling by the immunosuppressant tacrolimus in rheumatoid synoviocytes.
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.
Torigoshi
T
T
Clinical Research Center and Department of Rheumatology, NHO Nagasaki Medical Center, Nagasaki, Japan.
Motokawa
S
S
Miyashita
T
T
Maeda
Y
Y
Koga
T
T
Nakamura
M
M
Komori
A
A
Aiba
Y
Y
Uemura
T
T
Yatsuhashi
H
H
Ishibashi
H
H
Eguchi
K
K
Shindo
H
H
Migita
K
K
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*
D007166:Immunosuppressive Agents; D011965:Receptors, Glucocorticoid; D016559:Tacrolimus