The focus of this project is to define factors and signal transduction pathways involved in the modulation of human monocyte functions that may contribute to the immunopathology associated with various disease states. Connective tissue destruction is associated with many diseases in which the monocyte/macrophage is a prominent cell. Since matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) are believed to play a major role in the destruction and remodeling of connective tissue, a major emphasis has been placed on how these enzymes and inhibitors are controlled. Regulation of MMP-2 activation has been of considerable interest in light of its potential role in cancer progression. The recently described membrane-type metalloproteinases (MT- MMPs) form a family of membrane-bound enzymes that have as one of their functions the activation of MMP-2. Activation of monocytes with lipopolysaccharide or cytokines resulted in the expression of MT1-MMP on the surface of these cells. Monocyte MT1-MMP was shown to activate latent MMP-2 produced by fibroblasts and tumor cells. These findings indicate that MT1- MMP on tumor associated macrophages may have a significant role in determining the progression of tumors. Monocytes/macrophages also play a crucial role in cardiovascular diseases due to their potential to develop into foam cells, a prominent cell type found in atherosclerotic plaques. Since MMPs may be involved in the rupture of plaques resulting in the ischemic events associated with stroke and myocardial infarction, we are studying the effect of causative (oxidized LDL) and putative therapeutic agents (estrogen and raloxifene) for atherosclerosis on monocyte MMP production. These agents are being tested in vitro on normal monocytes and by examining functional responses of monocytes obtained from patients with high cholesterol/LDL levels that are on a clinical protocol involving treatment with estrogen and raloxifene. - Human Subjects
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