Background/Purpose: Synovial fibroblast plays a key role in rheumatoid arthritis (RA), which is a chronic polyarticular inflammatory disease. SF are able to migrate long distances in　vivo via the vasculature as previously shown in our SCID mouse migration model. In inflammatory processes, adipose tissue plays an important role as an endocrine organ. Some of its effects may be mediated by immunomodulating adipokines. RASF and endothelial cells (EC) are affected by adipokines in RA. The interaction between RASF and EC may be a crucial process in the migration of RASF through the vasculature.

Methods:

The expression of selected adhesion molecules from RASF and EC was analyzed by real-time PCR. For this purpose, primary RASF and EC were stimulated with adiponectin (10 µg/ml), visfatin (100　ng/ml) and resistin (20 ng/ml), and “therapeutically” with methotrexate (1.5 µM) and the glucocorticoids prednisolone (1 µM) and dexamethasone (1　µM).

RASF adhesion to EC 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 obtain their active conformation.

Results:

Under dynamic flow condition, which simulate the blood flow in vivo, the adhesion of RASF to EC was increased after stimulation with visfatin (+156%/+87%/+89%) and TNF-α (+61%/+18%/+19%). On the other hand, reduced adhesion was observed after stimulation with dexamethasone (-9%/-39%/-53%) and prednisolone (-31%/-64%/-53%). In EC, TNF-α upregulated the expression of ICAM-1 (47-fold; n=9), while adiponectin decreased it (-2.9-fold; n=5). The expression of VCAM-1 was slightly decreased after stimulation with adiponectin (-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. The expression of integrin α2 was upregulated after stimulation with resistin (2.8-fold; n=7) and TNF-α (13-fold; n=6). Only TNF-α increased the expression of ICAM-1 (40-fold; n=5) in RASF, while both visfatin (2.9-fold; n=10) and TNF-α (59-fold; n=9) increased the expression of VCAM-1 in RASF.

Conclusion:

During migration of RAFS in vivo, the adhesion of RASF to EC most likely plays a key role. Adipokines increase the adhesion of RASF to EC under dynamic flow conditions. Migration of RASF and spreading of RA to different joint could therefore be enhanced by the influence of adipokines on adhesion molecules and their effect strengthening the adhesion of RASF to EC. Glucocorticoids caused the opposite effect, which could explain some of the protective effects observed in patients. Adipokines alter the expression of adhesion molecules and the RASF/EC interaction with the effects differing between adipokines.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/adipokines-alter-the-interaction-between-rheumatoid-arthritis-synovial-fibroblasts-adhesion-and-endothelial-cells/