Abstract
Background: This study was performed to examine the effects of the Janus kinase (JAK) inhibitor peficitinib on fibroblast-like synoviocytes (FLS) obtained from patients with rheumatoid arthritis (RA). Methods: To examine the expression of JAK1, JAK2, and JAK3 in RA synovial tissue (ST) and FLS, immunohistochemistry was performed. We investigated the effects of peficitinib on interleukin 6 and IL-6 receptor responses in RA FLS. Phosphorylation of STAT was determined by western blot. To examine the functional analysis of peficitinib, we performed a proliferation and chemotaxis assays with FLS using THP-1 and peripheral blood mononuclear cells (PBMC). The inflammatory mediator expression of FLS was estimated by enzyme-linked immunosorbent assay. Results: JAK1, JAK2, and JAK3 were expressed in RA STs and FLS. Phosphorylation of STAT1, STAT3, and STAT5 in RA FLS was suppressed by peficitinib in a concentration-dependent manner. Peficitinib-treated RA FLS-conditioned medium reduced THP-1 and PBMC migration (p < 0.05) and proliferation of RA FLS (p < 0.05). Peficitinib suppressed the secretion of MCP-1/CCL2 in the RA FLS supernatant (p < 0.05). Conclusion: Peficitinib suppressed the JAK-STAT pathway in RA FLS and also suppressed monocyte chemotaxis and proliferation of FLS through inhibition of inflammatory cytokines.
Highlights
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammatory synovitis, cartilage and bone destruction, and several systemic features [1]
To determine whether JAK1, JAK2, and JAK3 were expressed in rheumatoid arthritis (RA) synovial tissue (ST), immunohistochemistry was performed
We found that JAK1, JAK2, and JAK3 were expressed in RA ST (Figure 1A)
Summary
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammatory synovitis, cartilage and bone destruction, and several systemic features [1]. In the intra-articular synovial tissue of RA patients, inflammatory cell infiltration by T lymphocytes, B lymphocytes, plasma cells, macrophages, neutrophils, mast cells, natural killer cells, and dendritic cells is witnessed. These inflammatory cells are activated, and inflammatory cytokines, such as tumor necrosis factor α (TNFα), and interleukin 6 (IL-6) are released [2]. Those cytokines proliferate and activate fibroblast-like synoviocytes (FLS), which secrete IL-6 and proteolytic enzymes to form pannus in joints thereby destroying cartilage and bone [3]. When the cytokines bind to membrane receptors, JAK is activated and STAT is phosphorylated to form [homo-dimers and hetero-dimers]. Phosphorylation of STAT1, STAT3, and STAT5 in RA FLS was suppressed by peficitinib in a concentration-dependent manner
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