The primary focus of our research is to define the 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 regulated. To address this question we are examining how biological mediators, such as cytokines, lipids and gram-negative bacterial, influence the mitogen-activated protein kinase and cyclooxygenase pathways involved in monocytge MMP and TIMP production. Current studies on the role of monocyte MMPs in various diseases have examined (a) how monocyte MT1-MMP may influence tumor metastasis through the activation of MMP-2 and (b) the impact of lipids, such as LDL and HDL, on monocyte MMP production as it relates to the immunopathology associated with atherosclerosis.