Endothelin-1 Modulates the Expression of Adhesion Molecules on Fibroblast-like Synovial Cells (FLS)

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Abstract
Endothelin-1 is known to possess various biological properties. In the present study we have investigated the effects of Endothelin-1 (Et-1) on the expression of adhesion molecules ICAM-1, VCAM-1 and CD-44 by fibroblast-like synoviocytes. Cultured fibroblast-like synoviocytes were treated with Et-1 in the absence or presence of C1306, a specific endothelin-A-receptor antagonist. Cell surface expression of ICAM-1, VCAM-1 and CD-44 was determined by immunofluorescence studies, Cyto-ELISA and FACS-analysis. ICAM-1, VCAM-1 and CD-44 were constitutively expressed on cultured FLS. After incubation with Et-1 the expression of ICAM-1, VCAM-1 and CD-44 increased. The level of expression of adhesion molecules after Et-1 stimulation was similar to cytokine mediated effects (IL-lβ, TNF-α). IL-iβ showed the strongest stimulatory effect on the expression of ICAM-1, TNF-α preferentially induced the expression of VCAM-1 and CD-44, and Et-1 strongly stimulated the upregulation of CD-44 expression. In addition, Et-1 enhanced significantly the IL-1β mediated upregulation of VCAM-1 expression, whereas TNF-α mediated expression of VCAM-1 was downregulated by Et-1. Furthermore, the Et-1 induced expression of adhesion molecules on FLS was mediated via the endothelin-A-receptor (EtA-receptor), since C-1306, a selective endothelin-A-receptor antagonist, could block this effect. These results indicate that Et-1 has stimulating effects on FLS in vitro. The expression of adhesion molecules can be upregulated by Et-1 similar to proinflammatory cytokines. The modulating effect of Et-1 can be inhibited by the pretreatment with a selective EtA-receptor antagonist. Thus, Et-1 may have immunoregulatory functions in the recruitment of cells infiltrating the inflamed tissue.