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.
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 alpha (TNF-alpha) 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-alpha- 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.
Zhang
Yahong
Y
Immunopathology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4352, USA.
Wahl
Larry M
LM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002097:C-Reactive Protein / Q000276:immunology / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology / Q000494:pharmacology*; D003324:Coronary Artery Disease / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D015232:Dinoprostone / Q000276:immunology / Q000494:pharmacology*; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000276:immunology / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D020781:Matrix Metalloproteinase 1 / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D010120:Oxytocics / Q000276:immunology / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D008077:Lipoproteins, LDL; D010120:Oxytocics; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002097:C-Reactive Protein; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone; D007213:Indomethacin