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

Carl Whatling, Hanna Björk, Sara Gredmark, Anders Hamsten, and Per Eriksson

King Gustaf V Research Institute, Stockholm SE-171 76

Corresponding Author: Per.Eriksson{at}medks.ki.se

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 effect of differentiation from monocytes to macrophages and exposure to mildly oxidized LDL on the expression of a range of proteinases and their inhibitors was assessed in the human THP-1 cell line. Of 56 proteinases/inhibitors investigated, seventeen were up-regulated during macrophage differentiation, including several 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 oxidized LDL increased expression of a control gene (ALBP) and increased the activity of NFkB and AP-1 in serum-free conditions, but did not significantly affect 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.

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