AB0081 The Inhibitory Effect of Synthetic Disease-Modifying Anti-Rheumatic Drugs and Steroids on Gliostatin/Platelet-Derived Endothelial Cell Growth Factor Production in Human Fibroblast-Like Synoviocytes. (9th June 2015)

• Record Type: Journal Article
• Authors: Kawaguchi, Y.; Waguri-Nagaya, Y.; Ikuta, K.; Tatematsu, N.; Kobayashi, M.; Goto, H.; Nozaki, M.; Aoyama, M.; Asai, K.; Otsuka, T.
• Is Part Of: Annals of the rheumatic diseases. Volume 74(2015)Supplement 2
• Page Start: 917
• Page End: 918
• Publication Date: 2015-06-09
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2015-eular.2471
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities. The expression of GLS in serum from patients with rheumatoid arthritis (RA) was significantly correlated with disease activity. We showed that GLS and angiogenic cytokine vascular endothelial growth factor (VEGF) have synergistic effects on angiogenesis in rheumatoid synovitis, and that GLS has a role in regulating VEGF. Objectives: Several synthetic disease-modifying anti-rheumatic drugs (DMARDs) have been used to control the progression of RA, although the mechanisms of their influence on angiogenesis remain obscure. The purpose of this study was to investigate whether synthetic DMARDs and steroids are involved in the regulation of GLS expression in Fibroblast-like synoviocytes (FLSs). Methods: FLSs obtained from patients with RA were cultured and stimulated by recombinant human (rHu) interleukin (IL)-1β with or without DMARDs and steroids. The expression levels of GLS were determined using the reverse transcription-polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA). Results: In cultured FLSs, GLS mRNA level was markedly increased by IL-1β treatment in a dose-dependent manner. The time course of GLS mRNA production stimulated by 0.1ng/ml rHuIL-1β showed a bell-shaped profile. By contrast, GLS levels in IL-1β-stimulated FLSs were reduced by pre-treatment with tofacitinib (TOF), FK506 (tacrolimus), aurothioglucose (AuTG) and dexamethasone (DEX). However, methotrexate (MTX) and sulfasalazine (SSZ) had no effects on GLS expression. Conclusions: The results of the present study demonstrate that GLS production in RA FLSs is stimulated by rHuIL-1β. We propose that a mode of action for tofacitinib, FK506, gold salts and DEX which is mediated by an inhibition of GLS. We therefore hypothesize that the suppression of GLS activity could be an effective therapy in RA. References: Kusabe T, et al. The inhibitory effect of disease-modifying anti-rheumatic drugs and steroids on gliostatin/platelet-derived endothelial cell growth factor production in human fibroblast-like synoviocytes. Rheumatol Int. 2005;25:625-530. Tanikawa T, et al. Gliostatin/thymidine phosphorylase-regulated vascular endothelial growth-factor production in human fibroblast-like synoviocytes. Rheumatol Int 2007;27:553–559. Yamagami T, et al. FK506 inhibition of gliostatin/thymidine phosphorylase production induced by tumor necrosis factor-α in rheumatoid fibroblast-like synoviocytes. Rheumatol Int 2011; 31:903-909. 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. Acknowledgements: 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, M. Aoyama: None declared, K. Asai: None declared, T. Otsuka: None declared