Impact of 4-hydroxynonenal on matrix metalloproteinase-9 regulation in lipopolysaccharide-stimulated RAW 264.7 cells.

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.