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), en dothelin-1 (ET-1) caused significant increases in mitogen-activated pr otein kinase (MAPK) activity, [H-3]thymidine incorporation, and cell p roliferation, confirming an activity of ET-1 as a potent mitogen on AO SMC. As an in vitro model to evaluate the significance of the mitogeni c activity of ET-1 on smooth muscle cells during atherogenesis, we stu died possible modulations of the responsiveness of the cells by treatm ent 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 cell s 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 res ponses, IL-1 beta treatment caused no changes in the responses induced by EGF, basic fibroblast growth factor, or PDGF, Studies on ET-l-indu ced 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 pro stanoid metabolism, These findings on AOSMC in vitro raise the possibi lity that, under some inflammatory conditions in vivo, ETs may work as a negative modulator of smooth muscle cell proliferation.