gms | German Medical Science

Background: Rheumatoid arthritis (RA) is a chronic polyarticular inflammatory disease. RA synovial fibroblasts (SF) play a key role in RA joint destruction. We showed their ability to migrate long distances in vivo in the SCID-mouse-model via the vasculature. Adipose tissue plays an active role in inflammation. Some of its effects may be mediated by adipokines due to their immunmodulatory potential. In RA, these adipokines have been shown to affect RASF and endothelial cells (EC). The interaction between both cells may be a crucial process in RASF migration.

Methods: RASF adhesion to EC was studied in a dynamic assay (flow rates: 18.4/30.5/60.5ml/h) as flow conditions are required for selectins to obtain their active conformation. Expression of adhesion molecules in RASF and EC was analyzed by real-time PCR. Primary RASF and EC were stimulated with adiponectin (10 µg/ml), visfatin (100 ng/ml) and resistin (20 ng/ml), with methotrexate (1.5 µM) and the glucocorticoids prednisolone (1 µM) and dexamethasone (1 µM).

Results: In the dynamic flow assay, RASF showed an increased adhesion to EC after stimulation with visfatin (+156%/+87%/+89%) and TNF-α (+61%/+18%+19%). Dexamethasone (-9%/-39%/-53%) and prednisolone (-31%/-64%/-53%) decreased the adhesion. Expression of integrin-α2 was upregulated by resistin (2.8-fold; n=7) and TNF-α (13-fold; n=6). Only TNF α increased ICAM-1 expression in RASF (40-fold; n=5), while visfatin (2.9 fold; n=10) and TNF-α (59-fold; n=9) increased the VCAM-1 expression in RASF. In EC, TNF-α upregulated ICAM-1 expression (47-fold; n=9) while adiponectin led to a decrease (-2.9-fold; n=5). Expression of VCAM-1 was slightly decreased after adiponectin stimulation (-1.3-fold; n=5) in EC whereas TNF-α led to a strong upregulation (235 fold; n=7). P-Selectin was down-regulated after stimulation with TNF-α (-8.6-fold; n=7) in EC.

Conclusion: The expression of adhesion molecules is strongly influenced by adipokines. Under flow conditions, adipokines increase adhesion of RASF to EC. The influence of adipokines on adhesion molecules and their enhancing effect on adhesion of RASF to EC could therefore further support the migration of RASF and subsequently the spreading of RA to distant areas. Of note, glucocorticoids showed the opposite effect, which could explain some of their clinical benefits observed in patients.