Matrix metalloproteinase-1 expression by interaction between monocytes andvascular endothelial cells

There is accumulating evidence of complicated interactions among vascular c ells, i.e. endothelial cells, smooth muscle cells and monocytes/macrophages , in the regulation of vascular function and remodeling. We have investigat ed the mechanisms responsible for matrix metalloproteinase (MMP)-1 expressi on by interactions between monocytes and vascular endothelial cells. THP-1 cells (human monocytic cell line) and human umbilical vein endothelial cell s (HUVECs) were cocultured. MMP-1 levels in the culture medium were measure d by enzyme-limited immunosorbent assays. Collagenolytic activity in the cu lture medium was measured by fluorescence labeled-collagen digestion. Immun ohistochemistry using an anti-MMP antibody was carried out to determine whi ch types of cell produce MMP-1. The addition of THP-1 cells to HUVECs for 4 8 h induced increases in MMP-1 levels and collagenolytic activity, which we re 5- and 2-fold relative to those of HUVECs alone, respectively. A separat e coculture experiment revealed that direct contact of THP-1 cells and HUVE Cs contributed to enhanced MMP-1 production in the cocolture. Immunohistoch emical analysis revealed that both types of cell produce MMP-1 in the cocul ture. Neutralizing anti-interleukin-1 beta and tumor necrosis factor-alpha antibodies inhibited MMP-1 production by the coculture, The Src kinase and MEK inhibitors significantly inhibited MMP-1 production by the coculture. C oculture of THP-1 cells and HUVECs induced significant increases in Src and mitogen activated protein (MAP) kinase activities. Enhanced MMP-1 expressi on induced by monocyte-endothelial cell interactions may play an important role in the pathogenesis of atherosclerosis and plaque rupture. (C) 2000 Ac ademic Press.