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(Journal of Leukocyte Biology. 2002;71:1012-1018.)
© 2002 by Society for Leukocyte Biology

Oxidized low-density and high-density lipoproteins regulate the production of matrix metalloproteinase-1 and -9 by activated monocytes

Immunopathology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland

Correspondence: Larry M. Wahl, Ph.D., Immunopathology Section, Building 30, Room 325, National Institute of Dental and Craniofacial Reseacrh, National Institutes of Health, Bethesda, MD 20892-4352. E-mail: lwahl{at}dir.nidcr.nih.gov

Monocytes/macrophages are prominent in atherosclerotic plaques where the vascular remodeling and plaque rupture may be influenced by the lipids and cytokines at these sites. Therefore, we evaluated the effects of factors found within the vascular wall, such as cytokines, oxidized low-density lipoprotein (ox-LDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), on monocyte-derived matrix metalloproteinase-1 (MMP-1) and -9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1). ox-LDL, LDL, and HDL alone had no effect on MMP-1, MMP-9, or TIMP-1 production. However, in the presence of tumor necrosis factor (TNF)- and GM-CSF, ox-LDL enhanced MMP-1 significantly by two- to threefold, increased MMP-9 slightly, and had no effect on TIMP-1 production. In contrast, HDL suppressed the induction of MMP-1 by TNF- and GM-CSF as well as the ox-LDL-mediated increase in MMP-1 production. The enhancement of MMP-1 production by ox-LDL occurred through, in part, a prostaglandin E₂ (PGE₂)-dependent pathway as indomethacin suppressed and PGE₂ restored MMP-1 production. This conclusion was supported further by ox-LDL-mediated increases in PGE₂ and cyclooxygenase-2 (COX-2) production. These data suggest that the interaction of primary monocytes with ox-LDL and proinflammatory cytokines may contribute to vascular remodeling and plaque rupture.

Key Words: atherosclerosis • prostaglandins • TNF- • GM-CSF

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