The Janus kinase inhibitor tofacitinib inhibits TNF-α-induced gliostatin expression in rheumatoid fibroblast-like synoviocytes.

Authors:
Yohei Kawaguchi
Yohei Kawaguchi
Nagoya City University Graduate School of Medical Science
Japan
Naoe Tatematsu
Naoe Tatematsu
Nagoya City University Graduate School of Medical Sciences
Yusuke Oguri
Yusuke Oguri
Food Resources Education and Research Center
Masaaki Kobayashi
Masaaki Kobayashi
Niigata University Medical and Dental Hospital
Niigata | Japan
Masahiro Nozaki
Masahiro Nozaki
Graduate School of Medical Sciences
Kiyofumi Asai
Kiyofumi Asai
Nagoya City University Graduate School of Medical Sciences
Nagoya | Japan
Mineyoshi Aoyama
Mineyoshi Aoyama
Nagoya City University Graduate School of Medical Sciences
Japan

Clin Exp Rheumatol 2018 Jul-Aug;36(4):559-567. Epub 2018 Jan 15.

Department of Orthopaedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Objectives: Gliostatin (GLS) is known to have angiogenic and arthritogenic activity, and GLS expression levels in serum from patients with rheumatoid arthritis (RA) are significantly correlated with the disease activity. Tofacitinib is a novel oral Janus kinase (JAK) inhibitor and is effective in treating RA. However, the mechanism of action of tofacitinib in fibroblast-like synoviocytes (FLSs) has not been elucidated. The purpose of this study was to investigate the modulatory effects of tofacitinib on serum GLS levels in patients with RA and GLS production in FLSs derived from patients with RA.

Methods: Six patients with RA who had failed therapy with at least one TNF inhibitor and were receiving tofacitinib therapy were included in the study. Serum samples were collected to measure CRP, MMP-3 and GLS expression. FLSs derived from patients with RA were cultured and stimulated by TNFα with or without tofacitinib. GLS expression levels were determined using reverse transcription-polymerase chain reaction (RT-PCR), EIA and immunocytochemistry, and signal transducer and activator of transcription (STAT) protein phosphorylation levels were determined by western blotting.

Results: Treatment with tofacitinib decreased serum GLS levels in all patients. GLS mRNA and protein expression levels were significantly increased by treatment with TNF-α alone, and these increases were suppressed by treatment with tofacitinib, which also inhibited TNF-α-induced STAT1 phosphorylation.

Conclusions: JAK/STAT activation plays a pivotal role in TNF-α-mediated GLS up-regulation in RA. Suppression of GLS expression in FLSs has been suggested to be one of the mechanisms through which tofacitinib exerts its anti-inflammatory effects.

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September 2018
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