Effect of macrophage differentiation and exposure to mildly oxidized LDL on the proteolytic repertoire of THP-1 monocytes

Lipid-laden monocyte/macrophages in atherosclerotic plaques can produce a range of proteinases capable of degrading components of the plaque extracellular matrix, an event that may weaken plaques, rendering them vulnerable to rupture. The effects of differentiation from monocytes to macrophages and exposure to mildly oxidized LDL (Ox-LDL) on the expression of a range of proteinases and their inhibitors were assessed in the human THP-1 cell line. Of 56 proteinases/inhibitors investigated, 17 were upregulated during macrophage differentiation, including several matrix metalloproteinases (MMPs) and cathepsins along with their native inhibitors. Similarly, expression of matrix-degrading proteinases was also increased during differentiation of human primary macrophages. In conjunction, the proteolytic capacity of the cells increased, as assessed by substrate zymography. Subsequent exposure of differentiated THP-1 cells to mildly Ox-LDL increased the expression of a control gene (adipocyte lipid binding protein) and increased the activity of nuclear factor-kappaB and activator protein-1 in serum-free conditions but did not significantly affect the expression of any of the proteinases or inhibitors investigated. These results indicate that in this model macrophage differentiation, rather than exposure to Ox-LDL, has a more important effect on the expression of genes involved in extracellular matrix remodeling.