Abstract
Rheumatoid arthritis (RA) is a worldwide chronic autoimmune inflammatory disease which is affecting approximately 1% of the total population. It is characterized by abnormal proliferation of fibroblast-like synoviocytes (FLS) and increased production of proinflammatory cytokines. In the current study, we were aiming to investigate the role of ubiquitin-specific protease 5 (USP5) in the inflammatory process in RA-FLS. Expression of USP5 was found upregulated in RA-FLS compared with that in osteoarthritis- (OA-) FLS, and IL-1β stimulation increased USP5 expression in a time-dependent manner. Furthermore, we found that USP5 overexpression significantly aggravated proinflammatory cytokine production and related nuclear factor κB (NF-κB) signaling activation. Consistently, silencing of USP5 decreased the release of cytokines and inhibited the activation of NF-κB. In addition, USP5 was found to interact with tumor necrosis factor receptor-associated factor 6 (TRAF6) and remove its K48-linked polyubiquitination chains therefore stabilizing TRAF6. Our data showed that a USP5-positive cell regulates inflammatory processes in RA-FLS and suggested USP5 as a potential target for RA treatment.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease and is characterized by the inflammation of joints, subsequent destruction of cartilage, and erosion of the bone [1, 2]
We investigated the expression of ubiquitin-specific protease 5 (USP5) in RA-fibroblast-like synoviocytes (FLS) and explored the function of USP5 in the inflammatory process in FLS cells
To the best of our knowledge, this is the first publication which shows the effect of USP5 in RA, and for the first time, we illustrate the target of USP5 in regulating the nuclear factor κB (NF-κB) signaling pathway
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease and is characterized by the inflammation of joints, subsequent destruction of cartilage, and erosion of the bone [1, 2]. The main clinical treatment strategy of RA is drug therapy, including immunosuppressive drugs and biological agents. These therapies induce a general drug resistance that increases the risk of infectious diseases and cancer [3]. It is of great significance to explore the mechanism of RA and identify new therapeutic targets. RA-FLS contribute to the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) that lead to cartilage destruction [6]. The central role of FLS in the progression of RA makes FLS considered for RA interventions in a therapeutic manner [7,8,9]
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