Background and objectives Rheumatoid Arthritis (RA) is a chronic polyarticular inflammatory disease. Adipose tissue, as an endocrine organ, also plays an important in inflammatory processes. RA synovial fibroblasts (SF) are able to migrate long distances in vivo via the vasculature as shown in a mouse model. Here, we analysed the role of adipokines, immunomodulatory factors mainly secreted by white adipose tissue, on RASF and endothelial cell (EC) adhesion. Static and dynamic adhesion and the expression of selected adhesion molecules on RASF and EC after stimulation with adipokines (adiponectin, visfatin, resistin), glucocorticoids and methotrexate (MTX) were evaluated.
Materials and methods Primary RASF and EC were stimulated with adiponectin (10 µg/ml), visfatin (100 ng/ml), resistin (20 ng/ml) and TNF-α (10ng/ml) as well as inhibited with MTX (1.5 µM), the glucocorticoids prednisolone (1 µM) and dexamethasone (1 µM). The interaction of both cell types under static conditions was analysed using a cell-to-cell-binding assay. RASF adhesion to E-selectin was studied in a flow adhesion assay (flow rates: 18.4/30.5/60.5 ml/h). Selected adhesion molecule expression on RASF and EC after adipokine/MTX/glucocorticoid stimulation was analysed by real-time PCR.
Results Prednisolone and dexamethasone stimulation down-regulated mRNA expression of VCAM-1 (prednisolone: -3.3-fold/dexamethasone: -8,3-fold) in RASF (n = 3). TNF-α, used as proinflammatory control, increased ICAM-1 mRNA expression (46.5 fold) in EC, while P-selectin mRNA expression (-7.7-fold) was decreased (n = 3). Under static conditions, the adipokines increased adhesion of RASF to EC (adiponectin: 37%, visfatin: 23%, resistin: 32%; n = 6), while prednisolone and MTX caused a minor decrease (-7% for both; n = 4). Dexamethasone 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 dexamethasone decreased their adhesion to E-selectin (-33%/-35%/-41%; n = 3 for each flow rate).
Conclusion Adipokines influence the cellular expression of adhesion molecules on RASF and EC as well as their interaction. Adipokines increase adhesion of RASF to EC and may thus affect RASF migration. Therapeutics such as glucocorticoids and MTX antagonised these effects, which could reflect the protective effects seen in clinics.