Abstract
Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities in the pathogenesis of rheumatoid arthritis (RA). The novel oral Janus kinase (JAK) inhibitor baricitinib has demonstrated high efficacy in RA. However, the effect of baricitinib on fibroblast-like synoviocytes (FLSs), a key component of invasive synovitis, has not been still elucidated. This study investigated whether GLS/TP production could be regulated by JAK/signal transducers and activators of transcription (STAT) signaling in FLSs derived from patients with RA. FLSs were cultured and stimulated by interferon (IFN)γ in the presence of baricitinib. Expression levels of GLS/TP were determined using reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunocytochemistry. Phosphorylation of STAT proteins was investigated by Western blot. In cultured FLSs, GLS/TP mRNA and protein levels were significantly induced by treatment with IFNγ and these inductions were suppressed by baricitinib treatment. Baricitinib inhibited IFNγ-induced STAT1 phosphorylation, while JAK/STAT activation played a pivotal role in IFNγ-mediated GLS/TP upregulation in RA. These results suggested that baricitinib suppressed IFNγ-induced GLS/TP expression by inhibiting JAK/STAT signaling, resulting in the attenuation of neovascularization, synovial inflammation, and cartilage destruction.
Highlights
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by hyperplastic inflammatory synovia and neovascularization [1]
We confirmed that IFNγ induced Gliostatin/thymidine phosphorylase (GLS/thymidine phosphorylase (TP)) mRNA and protein production in a dose-dependent manner and that 100 pg/ml IFNγ significantly increased the expression of GLS/TP (p < 0.001)
Our immunocytochemical studies revealed that GLS/ TP staining was weak and diffuse in the cytoplasm of Fibroblast-like synoviocytes (FLSs) in the absence of treatment
Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by hyperplastic inflammatory synovia and neovascularization [1]. Fibroblast-like synoviocytes (FLSs) are a key component of this inflammation and cause joint destruction by the production of growth factors, proangiogenic factors, and various cytokines and chemokines [2]. Pathogenetic pathways in RA involve T cells and B cells, macrophages, and monocytes with inflammatory cytokines such as tumor necrosis factor (TNF) α, interleukin (IL)-1β and IL-6, and interferon (IFN) γ. The action of these cytokines on synovial fibroblasts, chondrocytes, and osteoclasts leads to joint destruction [3,4,5]. Gliostatin (GLS) has thymidine phosphorylase (TP) activity and is known as platelet-derived endothelial cell growth factor (PD-ECGF) [7].
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