Potentiation of glucocorticoid receptor (GR)-mediated signaling by the immunosuppressant tacrolimus in rheumatoid synoviocytes.

Clin Exp Rheumatol. 2009 Mar-Apr;27(2):246-52
Authors: Torigoshi T, Motokawa S, Miyashita T, Maeda Y, Koga T, Nakamura M, Komori A, Aiba Y, Uemura T, Yatsuhashi H, Ishibashi H, Eguchi K, Shindo H, Migita K
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. CONCLUSION: 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.
PMID: 19473564 [PubMed – indexed for MEDLINE]