Background The JAK/STAT signaling pathways mediate the effects of many cytokines and growth factors related rheumatoid arthritis (RA). Tofacitinib is a novel oral JAK inhibitor and it has demonstrated high efficacy in RA, even in non-responder to anti-TNF treatment. Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities. GLS/TP was expressed in inflamed synovial tissues of patients with RA. In cultured fibroblast-like synoviocytes (FLSs), GLS/TP expression was found to be up-regulated by inflammatory cytokines, such as IL-1β, TNFα. GLS acted as a cytokine in FLSs, augmenting its own synthesis, and also induced the extracellular secretion of matrix metalloproteinase (MMP)-1, and MMP-3. Therefore the suppression of GLS production might be an effective therapy in RA. Tofacitinib inhibits the function of T cells, however the mechanism of the action of tofacitinib had not been determined in fibroblast- like synoviocytes.
Objectives The purpose of this study was to investigate the effect of tofacitinib on GLS production in FLSs derived from patients with RA (RAFLSs).
Methods RAFLSs were cultured and stimulated by tumor necrosis factor (TNF)-α with or without treatment of tofacitinib. The expression levels of GLS were determined using reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay and immunocytochemistry.
Results In cultured RAFLSs, GLS mRNA and protein levels were significantly induced by stimulation with TNFα alone and these GLS/TP inductions were significantly suppressed by treatment of tofacitinib in a dose-dependent manner.
Conclusions Our data demonstrated that JAK/STAT activation play a pivotal role in TNF mediated GLS up-regulation in RAFLSs. Suppression of GLS production in inflamed synovia has been suggested as one of the anti-inflammatory effects of tofacitinib.
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Acknowledgement This research was spportded by Grand-in-Aid for Scientific Research (C) (26462309) from the Japan Society for the Promotion of Science.
Disclosure of Interest Y. Kawaguchi: None declared, Y. Waguri-Nagaya Grant/research support from: Biomet Japan, Inc, Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Merck Sharp & Dohme Co., AbbVie Japan Co., Ltd., Ono Pharmaceutical Co., Ltd., K. Ikuta: None declared, N. Tatematsu: None declared, M. Kobayashi: None declared, H. Goto: None declared, M. Nozaki: None declared, K. Asai: None declared, T. Otsuka: None declared
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