Effect of cytokines on the production of endothelin by endothelial cells.

OBJECTIVE

Circulating levels of endothelin (ET), a potent vasoconstrictor peptide and a mitogen for smooth muscle cells and fibroblasts, are reported to be increased in a variety of human diseases characterized by vascular pathology. In view of the probable immune bases for vascular injury in connective tissue disorders, we examined the effect of the cytokines IL-1 alpha, IL-4, IL-6, TNF-alpha and lymphotoxin on the production of ET-1 by cultured vascular endothelial cells.

RESULTS

ET levels in endothelial cell conditioned media were measured by radioimmunoassay. IL-4 and lymphotoxin had no effect on ET release by endothelial cells, while IL-6, TNF-alpha and IL-1 alpha stimulated ET mRNA expression and ET release in a dose dependent fashion. IL-6 was the most potent stimulator and IL-1 was the least effective. The addition of neutralizing antibodies to the cytokines inhibited the observed increase in ET release.

CONCLUSIONS

These results suggest that cytokines may play a significant role in the control of vascular tone. Furthermore, cytokines may indirectly contribute to the development of proliferative vascular lesions by stimulating smooth muscle and interstitial cell proliferation through their effects on endothelin release by the vascular endothelium.