FK506 inhibition of gliostatin/thymidine phosphorylase production induced by tumor necrosis factor-α in rheumatoid fibroblast-like synoviocytes

Abstract

Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities. The purpose of this study was to determine the inhibitory effects of FK506 (tacrolimus) on GLS production in rheumatoid arthritis (RA). We investigated the modulation of serum GLS by FK506 therapy and the effect of FK506 on the production of GLS in fibroblast-like synoviocytes (FLSs). Serum samples were collected from 11 RA patients with active disease at baseline and after 12 weeks of FK506 treatment. Serum concentrations of GLS and matrix metalloproteinase (MMP)-3 were measured by ELISA and found to be down-regulated in responders evaluated with a disease activity score. Patient FLSs were cultured and stimulated by tumor necrosis factor (TNF)-α with or without FK506. The expression levels of GLS were determined using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme immunoassay and shown to be significantly increased. GLS levels in TNF-α-stimulated FLSs were reduced by FK506 treatment. Our data show a novel mechanism for the action of physiological concentrations of FK506 in RA that regulates the production of GLS in FLSs.

Thymidine Phosphorylase Regulates the Expression of CXCL10 in Rheumatoid Arthritis Fibroblast‐like Synoviocytes

“…Kusabe et al showed that antirheumatic drugs such as aurothioglucose and dexamethasone suppressed IL‐1β–induced TP expression in FLS (). These investigators also demonstrated that the immunosuppressant FK‐506 (tacrolimus), which has been approved as an antirheumatic drug in Japan, inhibited the level of TP that was increased by TNFα (). We confirmed that aurothioglucose and FK‐506 suppressed the expression of TYMP and CXCL10 mRNA in RA FLS (data not shown).…”

The Janus kinase inhibitor (baricitinib) suppresses the rheumatoid arthritis active marker gliostatin/thymidine phosphorylase in human fibroblast-like synoviocytes

“…It remains unknown whether IFNγ acts directly on FLSs. GLS/TP has IFNγ binding sites in the promoter region [ 17 ]; therefore, we focused on the direct effect of IFNγ on GLS/TP production in RA FLSs.…”

“…In addition, the combination of TNFα and IFNγ synergistically augmented the expression of GLS/TP in FLSs [ 15 ]. We previously reported that direct injection of GLS/TP into rabbit knees led to pronounced RA-like synovitis [ 16 ], and that serum GLS/TP levels were decreased in RA patients treated with tacrolimus, one of the conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) [ 17 ], and with surgeries such as synovectomy and total joint arthroplasty [ 18 ]. We reported that the GLS/TP promoter has seven Sp-1 binding sites and that the Sp-1 inhibitor mithramycin suppressed GLS/TP production in FLSs [ 19 ].…”

Effects of low-dose tacrolimus therapy in combination with methotrexate in patients with methotrexate-refractory rheumatoid arthritis

“…7 Yamagami T et al showed a novel mechamism for the action of physiological concentrations of FK506 in RA that regulates the production of glistatin/thymidine phosphorylase in fibroblast-like synoviocytes. 8 There are many reports about the efficacy and safety to RA patients. 9 – 11 Moreover, there is also a report to systemic lupus erytematosus, 12 Churg–Strauss symdrome, 13 and the RA associated with MDS.…”