EFFECT OF CYTOKINES ON THE PRODUCTION OF ENDOTHELIN BY ENDOTHELIAL-CELLS

Objective. Circulating levels of endothelin (ET), a potent vasoconstri ctor peptide and a mitogen for smooth muscle cells and fibroblasts, ar e reported to be increased in a variety of human diseases characterize d by vascular pathology. In view of the probable immune bases for vasc ular 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. E T levels in endothelial cell conditioned media were measured by radioi mmunoassay. IL-4 and lymphotoxin had no effect on ET release by endoth elial cells, while IL-6, TNF-alpha and IL-1 alpha stimulated ET mRNA e xpression and ET release in a dose dependent fashion. IL-6 was the mos t potent stimulator and IL-1 was the least effective. The addition of neutralizing antibodies to the cytokines inhibited the observed increa se in ET release. Conclusions. These results suggest that cytokines ma y play a significant role in the control of vascular tone. Furthermore , cytokines may indirectly contribute to the development of proliferat ive vascular lesions by stimulating smooth muscle and interstitial cel l proliferation through their effects on endothelin release by the vas cular endothelium.