Background As an endocrine organ, adipose tissue plays a crucial role in inflammatory processes. These can be mediated by adipokines, important factors secreted by adipose tissue, displaying pro- or anti-inflammatory effects. Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, in which joints are consecutively affected. We previously showed that within the murine organism RA synovial fibroblasts (SF) are able to migrate from one site to another. This may contribute to the spreading of the disease in vivo. Due to the observation that in this model RASF migrate through the vasculature, the interaction between RASF and endothelial cells appears to be critical in this process.
Objectives To assess whether adipokines affect the adhesion of RASF to endothelial cells (EC) or surface molecules expressed by EC (here: E-selectin) and to identify relevant adhesion molecules whose expression is altered by adipokines.
Methods RASF and EC were stimulated with the adipokines adiponectin (Ad) (10 μg/ml), visfatin (Vis) (100 ng/ml) and resistin (Res) (20 ng/ml), and “therapeutically” with methotrexate (MTX) (1.5 μM) and the glucocorticoids prednisolone (PNL) (1 μM) and dexamethasone (DXM) (1 μM). The expression of selected adhesion molecules from RASF and EC was analyzed by real-time PCR. RASF adhesion to EC was studied under static conditions using a cell-to-cell binding assay, while RASF adhesion to E-selectin was studied under flow conditions (flow rates: 18.4/30.5/60.5 ml/h) in a dynamic adhesion assay as flow conditions are required for selectins to be obtain their active conformation.
Results Under static conditions, the adipokines caused an increased adhesion of RASF to EC (Ad: 37%, Vis: 23%, Res: 32%; n=6), while PNL and MTX caused a minor decrease (-7% for both; n=4). DXM did not change RASF adhesion to EC under static conditions. Under flow conditions, visfatin increased RASF adhesion to E-selectin (28%/87%/29%; n=3 for each flow rate), while DXM decreased their adhesion ability (-33%/-35%/-41%; n=3 for each flow rate). mRNA expression of VCAM-1 in RASF (n=3) was reduced by stimulation with PLN (-3.3-fold) and DXM (-8.3-fold), respectively. TNF increased ICAM-1 mRNA expression (46.5 fold) and decreased P-selectin mRNA expression (-7.7-fold) in EC (n=3).
Conclusions Adipokines increase the cellular expression of adhesion molecules on RASF as well as EC and strengthen their interaction. This increased adhesion of RASF to endothelial cells mediated by adipokines could therefore influence the migration of RASF and thus the spreading of RA in vivo. As glucocorticoids and MTX antagonized these effects, our experiments can also explain some of the clinical effects observed in patients.
Disclosure of Interest None declared