SUPPRESSION OF ENDOTHELIN-L-INDUCED MITOGENIC RESPONSES OF HUMAN AORTIC SMOOTH-MUSCLE CELLS BY INTERLEUKIN-1-BETA

When applied to quiescent human aortic smooth muscle cells (AOSMC), endothelin-1 (ET-1) caused significant increases in mitogen-activated protein kinase (MAPK) activity, [H-3]thymidine incorporation, and cell proliferation, confirming an activity of ET-1 as a potent mitogen on AOSMC. As an in vitro model to evaluate the significance of the mitogenic activity of ET-1 on smooth muscle cells during atherogenesis, we studied possible modulations of the responsiveness of the cells by treatment with various cytokines (IL-1 beta, IL-8, TNF alpha, and TGF beta), Of the four cytokines tested, we found that the treatment of the cells with IL-1 beta dramatically reduced the responsiveness of the cells to ET-1; IL-1 beta treatment at the concentration of 0.2 ng/ml for 8 h completely abolished the activity of ET-1 to induce the mitogenic responses, IL-1 beta treatment caused no changes in the responses induced by EGF, basic fibroblast growth factor, or PDGF, Studies on ET-l-induced intracellular signaling events in IL-1 beta-treated cells revealed that the failure of ET-1 to induce mitogenic responses was due to an increase in cAMP formation secondary to ET-l-induced activation of prostanoid metabolism, These findings on AOSMC in vitro raise the possibility that, under some inflammatory conditions in vivo, ETs may work as a negative modulator of smooth muscle cell proliferation.