title: Impact of 4-hydroxynonenal on matrix metalloproteinase-9 regulation in lipopolysaccharide-stimulated RAW 264.7 cells.
abstract: Tissue degradation and leukocyte extravasation suggest proteolytic destruction of the extracellular matrix (ECM) during severe malaria. Matrix metalloproteinases (MMPs) play an established role in ECM turnover, and increased MMP-9 protein abundance is correlated with malarial infection. The malaria pigment hemozoin (Hz) is a heme detoxification biomineral that is produced during infection and associated with biologically active lipid peroxidation products such as 4-hydroxynonenal (HNE) adsorbed to its surface. Hz has innate immunomodulatory activity, and many of its effects can be reproduced by exogenously added HNE. Hz phagocytosis enhances MMP-9 expression in monocytes; thus, this study was designed to examine the ability of HNE to alter MMP-9 regulation in activated cells of macrophage lineage. Data show that treatment of lipopolysaccharide-stimulated RAW 264.7 cells with HNE increased MMP-9 secretion and activity. HNE treatment abolished the cognate tissue inhibitor of metalloproteinase-1 protein levels, further decreasing MMP-9 regulation. Phosphorylation of both p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase was induced by HNE, but only p38 MAPK inhibition lessened MMP-9 secretion. These results demonstrate the in vitro ability of HNE to cause MMP-9 dysregulation in an activated cell model. The findings may extend to myriad pathologies associated with lipid peroxidation and elevated MMP-9 levels leading to tissue damage.
authors: Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
authors: Alexandra C
authors: AC
authors: Schrimpe-Rutledge
authors: Kim Y
authors: KY
authors: Fong
authors: David W
authors: DW
authors: Wright
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015227:Lipid Peroxidation; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D008070:Lipopolysaccharides; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C027576:4-hydroxy-2-nonenal
keywords: 4-hydroxynonenal; hemozoin; malaria; matrix metalloproteinase-9; tissue inhibitor of metalloproteinase-1