The nuclear factor-κB (NF-κB) signaling pathway regulates multiple processes in innate and adaptive immune cells. This pathway is involved in inflammation through the regulation of cytokines, chemokines, and adhesion molecules expression. The NF-κB transcription factor also participates in the survival, proliferation, and differentiation of cells. Therefore, deregulated NF-κB activation contributes to the pathogenesis of inflammatory diseases. Rheumatoid arthritis (RA) is classified as a heterogeneous and complex autoimmune inflammatory disease. Although different immune and non-immune cells contribute to the RA pathogenesis, fibroblast-like synoviocytes (FLSs) play a crucial role in disease progression. These cells are altered during the disease and produce inflammatory mediators, including inflammatory cytokines and matrix metalloproteinases, which result in joint and cartilage erosion. Among different cell signaling pathways, it seems that deregulated NF-κB activation is associated with the inflammatory picture of RA. NF-κB activation can also promote the proliferation of RA-FLSs as well as the inhibition of FLS apoptosis that results in hyperplasia in RA synovium. In this review, the role of NF-κB transcription factor in immune and non-immune cells (especially FLSs) that are involved in RA pathogenesis are discussed.
Fibroblast-like synoviocytes (FLSs) have been introduced in recent years as a key player in the pathogenesis of rheumatoid arthritis (RA), but the exact mechanisms of their transformation and intracellular pathways have not yet been determined. This study aimed to investigate the role of fibroblast activation protein-alpha (FAP-α) in the regulation of genes involved in the transformation and pathogenic activity of RA FLSs. Synovial FLSs were isolated from RA patients and non-arthritic individuals (n=10 in both groups) and characterized; using immunocytochemistry and flow cytometry analysis. FLSs were divided into un-treated and Talabostat-treated groups to evaluate the FAP-α effect on the selected genes involved in cell cycle regulation (p21, p53, CCND1), apoptosis (Bcl-2, PUMA), and inflammatory and destructive behavior of FLSs (IL-6, TGF-β1, MMP-2, MMP-9, P2RX7). Gene expression analysis was performed by quantitative real-time polymerase chain reaction (qRTPCR), and immunoblotting was carried out to evaluate FAP-α protein levels. The basal level of FAP-α protein in RA patients was significantly higher than non-arthritic control individuals. However, no differences were observed between RA and non-arthritic FLSs, at the baseline mRNA levels of all the genes. Talabostat treatment significantly reduced FAPα protein levels in both RA and non-arthritic FLSs, however, had no effect on mRNA expressions except an upregulated TGF-β1 expression in non-arthritic FLSs. A significantly higher protein level of FAP-α in FLSs of RA patients compared with that of healthy individuals may point to the pathogenic role of this protein in RA FLSs. However, more investigations are necessary to address the mechanisms mediating the FAP-α pathogenic role in RA FLSs.
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