Downregulation of intercellular adhesion molecule-1 expression on human synovial fibroblasts by endothelin-1

Objective. To study the effect of endothelin-1 (ET-1) on the expression of intercellular adhesion molecule-1 (ICAM-1) by synovial fibroblasts derived from individuals with rheumatoid arthritis (RA) or osteoarthritis (OA). Methods. The expression of ICAM-1 protein and the abundance of ICAM-1 mRNA in synovial fibroblasts derived from individuals with RA or OA, or healthy controls, was assessed by now cytometry and Northern blot analysis, respect ively. mRNA expression of ET type A (ETA) and ET type B (ETB) receptors was assessed by reverse transcription polymerase chain reaction. Results. Tumor necrosis factor-alpha (TNF-alpha) increased the expression o f ICAM-1 by RA and OA fibroblasts. While ET-1 alone had no significant effe ct an ICAM-1 expression by either cell type, it inhibited the TNF-alpha ind uced increase in ICAM-1 expression, and this effect was more marked in RA f ibroblasts. TNF-alpha also increased the amount of ICAM-1 mRNA in both cell types, and ET-1 inhibited this increase to a greater extent in RA fibrobla sts than in OA fibroblasts. This inhibitory effect of ET-1 was reversed by addition of specific antagonist of ETA receptor, mRNA expression of ETA and ETB receptors was significantly greater in RA fibroblasts stimulated with TNF-alpha or even medium alone than in OA fibroblasts. Conclusion, These results suggest that ICAM-1 expression by fibroblasts is regulated not only by proinflammatory cytokines such as TNF-alpha and inter leukin- 1 beta, but also by the vasoactive peptide ET-1, and that ET-1 may play an important role in inflammatory responses, especially in rheumatoid synovitis.