Glucocorticoids increase α5 integrin expression and adhesion of synovial fibroblasts but inhibit ERK signaling, migration, and cartilage invasion

Abstract

Objective. In rheumatoid arthritis (RA), integrins mediate cell adhesion, migration, and invasion, and their expression is regulated by cytokines and growth factors. The aim of this study was to investigate whether hormones such as cortisol or other steroids can influence integrin expression and function in the synovial cells of patients with RA.Methods. We performed immunofluorescence and fluorescence-activated cell sorting analyses to quantify surface integrin levels. Adhesion and migration assays were performed to study the function of synovial fibroblasts (SFs). ERK activation was measured by cellular activation of a signaling enzyme-linked immunosorbent assay. Invasion of SFs into cartilage was determined in the SCID mouse coimplantation model of RA in vivo.Results. In RA, expression of integrin subunits ␣5, ␣v, and ␤1 was higher at the site of invasion compared with the sublining zone. Testosterone and 17␤-estradiol had no influence on integrin levels, but cortisol up-regulated expression of the ␣5 subunit in a time-dependent and dose-dependent manner. In addition, cortisol increased the adhesion of SFs to fibronectin and inhibited ERK signaling upon integrin activation or upon stimulation with tumor necrosis factor. Small interfering RNA or a neutralizing antibody to ␣5 integrin increased SF migration, indicating that upregulated ␣5 integrin is responsible for an immobile phenotype. In addition, in the SCID mouse model, SF invasion into cartilage was attenuated by glucocorticoid treatment in vivo.Conclusion. Glucocorticoids increase integrin expression and the adhesion of cells to fibronectin, inhibit ERK signaling, and down-regulate the invasiveness of SFs in vivo. This study demonstrates that an important antiinflammatory aspect of glucocorticoids is regulating the expression and function of ␣5 integrin.

Aspergillus fumigatus CalA binds to integrin α5β1 and mediates host cell invasion

“…These results indicate that CalA mediates pulmonary invasion, and that invasion of host cells plays a key role in the pathogenesis of invasive pulmonary aspergillosis. CalA may play an especially prominent role in pathogenicity during infection in the presence of corticosteroids, which enhance expression of integrin α5 by some host cells 32 . Proteins such as CalA that are expressed on the fungal cell surface are promising therapeutic targets because of their accessibility.…”

Tetraspanin CD82 affects migration, attachment and invasion of rheumatoid arthritis synovial fibroblasts

“…The strongest colocalisation with CD82 was present in the endothelium, supporting the role of endothelium in RASF recruitment and mobility. The RASF recruitment and the increased integrin expression at the site of cartilage invasion is well known 39. However, the CD82-induction at sites of cartilage erosion may contribute to hold activated RASF on-site.…”

Integrins and their ligands in rheumatoid arthritis

“…Several groups have investigated synovial tissue samples and isolated cells to study integrin expression. The integrin subunit β1 is most widely expressed since it can be found on macrophages, lymphocytes, endothelial cells, and fibroblasts [5,15,16]. The fibronectin receptor α5β1 and the laminin receptor α3β1 were also found on every synovial cell type, whereas α4β1, which besides fibronectin also binds VCAM-1, was found only on lymphocytes.…”

“…In synovial tissue, integrin expression also depends on the location of the particular cell. Expression of most integrins is similar throughout the synovial tissue but is different at the synovial lining layer [5]. This is the area where synovial cells adhere to cartilage and activated fibroblasts and macrophages degrade ECM and invade cartilage.…”

“…In some aspects, they can be considered 'tumor-like' as SFs are resistant to many apoptotic pathways, show increased proliferation, and produce high amounts of matrix metalloproteinases (MMPs) because of dysregulation of the transcription factors AP-1, p53, and nuclear factor-kappa-B (NF-κB) [4]. Fibroblasts, macrophages, but also endothelial cells in synovial tissue show high levels of integrin expression [5]. In RA, not only integrins but also their ligands (for example, fibronectin and collagen as well as their degradation products) are up-regulated [6].…”