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Published online before print October 21, 2005

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(Journal of Leukocyte Biology. 2006;79:105-113.)
© 2006 by Society for Leukocyte Biology

Synergistic enhancement of cytokine-induced human monocyte matrix metalloproteinase-1 by C-reactive protein and oxidized LDL through differential regulation of monocyte chemotactic protein-1 and prostaglandin E₂

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

¹ Correspondence: Immunopathology Section, 30 Convent Drive, Building 30, Room 3A-300, NIDCR/NIH, Bethesda, MD 20892-4352. E-mail: lwahl{at}dir.nidcr.nih.gov

C-reactive protein (CRP) and oxidized LDL (ox-LDL) are associated with inflammatory lesions, such as coronary artery disease, in which monocytes and matrix metalloproteinases (MMPs) may play a major role in the rupture of atherosclerotic plaques. Monocytes are recruited to inflammation sites by monocyte chemoattractant protein-1 (MCP-1), which may also participate in the activation of monocytes. The objective of this study was to compare the individual and combined effect of CRP and ox-LDL on human monocyte MMP-1 and the role of MCP-1 in this effect. Although CRP or ox-LDL failed to induce MMP-1 in control monocytes, these molecules enhanced MMP-1 production induced by tumor necrosis factor (TNF-) and granulocyte macrophage-colony stimulating factor (GM-CSF) with a synergistic increase in MMP-1 occurring in the presence of both mediators. Enhancement of MMP-1 by CRP and ox-LDL was attributable to a differential increase in MCP-1 and prostaglandin E₂(PGE₂). CRP, at physiological concentrations, induced high levels of MCP-1 and relatively low levels of PGE₂, whereas ox-LDL caused a significant enhancement of PGE₂ with little affect on MCP-1. Accordingly, CRP- and ox-LDL-induced MMP-1 production by monocytes was inhibited by anti-MCP-1 antibodies and indomethacin, respectively. Moreover, addition of exogenous MCP-1 or PGE₂ enhanced MMP-1 production by TNF-- and GM-CSF-stimulated monocytes. These results show that the combination of CRP and ox-LDL can cause a synergistic enhancement of the role of monocytes in inflammation, first, by increasing MCP-1, which attracts more monocytes and directly enhances MMP-1 production by activated monocytes, and second, by elevating PGE₂ production, which also leads to higher levels of MMP-1.

Key Words: tumor necrosis factor • granulocyte macrophage-colony stimulating factor • inflammation • atherosclerosis

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