Interleukin-8 (IL-8) is a chemokine produced by a variety of cell types involved in atherogenesis and is chemotactic for neutrophils and lymphocytes. A recent study has shown that IL-8 is angiogenic and induces proliferation and chemotaxis of endothelial cells. The present study was undertaken to find out whether IL-8 is also mitogenic and chemotactic for vascular smooth muscle cells. IL-8 induced a concentration-dependent (0.1 to 10 nmol/L) stimulation of DNA synthesis and cell proliferation in both human and rat aortic smooth muscle cells. In addition, IL-8 stimulated smooth muscle cells to produce prostaglandin E(2), which can inhibit IL-8-induced smooth muscle cell proliferation. In the presence of indomethacin (5 mu mol/L), IL-8 (1 nmol/L) stimulated an increase in human and rat aortic smooth muscle cell number during a 3-day period of incubation by 61+/-16% and 59+/-7% (n=4), respectively. IL-8 also increased DNA synthesis in human and rat aortic smooth muscle cells by 98+/-10% and 151+/-27% (n=5), respectively. Moreover, IL-8 stimulated rat aortic smooth muscle cell migration by 20-fold over the control value, with an EC(50) value of 0.83 nmol/L; this chemotactic activity of IL-8 was also potentiated by indomethacin. Exposure of smooth muscle cells to IL-8 caused rapid and transient expression of the immediate-early genes c-fos and zif268 mRNA. The maximal levels of c-fos and zif268 mRNA in human and rat aortic smooth muscle cells were observed 30 minutes and 1 hour after stimulation with IL-8, respectively, followed by rapid decline. Moreover, IL-8 stimulated mitogen activated protein (MAP) kinase in smooth muscle eels with a peak at 5 to 10 minutes after stimulation. At 1 and 10 nmol/L IL-8, MAP kinase activity increased by 1.5- and 7-fold above the basal level, respectively. Since vascular smooth muscle cell proliferation and migration are crucial steps in neointimal formation in restenosis and atherosclerosis, these results suggest that IL-8 may be an important naturally occurring mitogen and chemoattractant for vascular smooth muscle cells and may play a role in the pathogenesis of arterial intimal thickening and atherosclerosis.
