ENDOTHELIN-1 MODULATES THE EXPRESSION OF ADHESION MOLECULES ON FIBROBLAST-LIKE SYNOVIAL-CELLS (FLS)

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 f ibroblast-like synoviocytes. Cultured fibroblast-like synoviocytes wer e treated with Et-1 in the absence or presence of C1306, a specific en dothelin-A-receptor antagonist. Cell surface expression of ICAM-1, VCA M-1 and CD-44 was determined by immunofluorescence studies, Cyto-ELISA and FACS-analysis. ICAM-1, VCAM-1 and CD-44 were constitutively expre ssed on cultured FLS. After incubation with Et-1 the expression of ICA M-1, VCAM-1 and CD-44 increased. The level of expression of adhesion m olecules after Et-1 stimulation was similar to cytokine mediated effec ts (IL-1 beta: TNF-alpha). IL-1 beta showed the strongest stimulatory effect on the expression of ICAM-1, TNF-alpha preferentially induced t he expression of VCAM-1 and CD-44, and Et-1 strongly stimulated the up regulation of CD-44 expression. Ln addition, Et-1 enhanced significant ly the IL-1 beta mediated upregulation of VCAM-1 expression, whereas T NF-alpha mediated expression of VCAM-1 was downregulated by Et-1. Furt hermore, the Et-1 induced expression of adhesion molecules on FLS was mediated via the endothelin-A-receptor (Et(A)-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 v itro. The expression of adhesion molecules can be upregulated by Et-1 similar to proinflammatory cytokines. The modulating effect of Et-1 ca n be inhibited by the pretreatment with a selective Et(A)-receptor ant agonist. Thus, Et-1 may have immunoregulatory functions in the recruit ment of cells infiltrating the inflamed tissue.