Background: The JAK/STAT signaling pathways mediate the production of many cytokines and growth factors related rheumatoid arthritis (RA) . Baricitinib is a novel oral JAK inhibitor and it has demonstrated high efficacy in RA . Gliostatin (GLS) is known to have angiogenic and arthritogenic activities. GLS was expressed in inflamed synovial tissues of patients with RA. In cultured fibroblast-like synoviocytes (FLSs), GLS 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, -3, -9, and -13 . Therefore the suppression of GLS production might be an effective therapy in RA. The mechanism of the action of baricitinib had not been determined in fibroblast-like synoviocytes (FLSs).
Objectives: The purpose of this study was to investigate the GLS production effect of interferon (IFN) γ and the inhibitory action of baricitinib in FLSs derived from patients with RA (RA-FLSs).
Methods: RA-FLSs were cultured from synovial specimens of patients with RA and stimulated by IFNγ with or without treatment of baricitinib. The expression levels of GLS were determined using reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay and immunocytochemistry.
Results: In cultured RA-FLSs, GLS mRNA and protein were significantly induced by stimulation with IFNγ and these GLS inductions were significantly suppressed by treatment of baricitinib in dose-dependent manners.
Conclusion: Our data demonstrated that JAK/STAT activation play a pivotal role in IFNγ mediated GLS up-regulation in RA-FLSs. Suppression of GLS production in inflamed synovia has been suggested as one of the anti-inflammatory effects of baricitinib.
References  Kawaguchi Y, et al. The Janus kinase inhibitor tofacitinib inhibits TNF-α-induced gliostatin expression in rheumatoid fibroblast-like synoviocytes. Clin Exp Rheumatol. 2018;36:559-567.
 Vollenhoven R, et al. Safety and Efficacy of Baricitinib in Patients Receiving Conventional Synthetic Disease-Modifying Antirheumatic Drugs or Corticosteroids. Rheumatol Ther 2018; 5:525–536.
 Ikuta K, et al. The Sp1 transcription factor is essential for the expression of gliostatin/thymidine phosphorylase in rheumatoid fibroblast-like synoviocytes. Arthritis Research & Therapy 2012; 14:R87.
 Tatematsu N, et al. Mithramycin has inhibitory effects on gliostatin and matrix metalloproteinase expression induced by gliostatin in rheumatoid fibroblast-like synoviocytes. Mod Rheumatol. 2018;28:495-505.
Acknowledgement: This research was supported by Grand-in-Aid for Scientific Research(C)(26462309) from the Japan Society for the Promotion of Science.
Disclosure of Interests: None declared
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