Published online before print September 4, 2008

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(American Journal of Pathology. 2008;173:1057-1066.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071150

Inhibition of the Lipopolysaccharide-Induced Stimulation of the Members of the MAPK Family in Human Monocytes/Macrophages by 4-Hydroxynonenal, a Product of Oxidized Omega-6 Fatty Acids

Christos Marantos^*, Violet Mukaro, Judith Ferrante, Charles Hii and Antonio Ferrante^*

From The Sansom Institute and School of Pharmacy and Medical Sciences,^* University of South Australia, Adelaide; the Department of Immunopathology, Children, Youth, and Women’s Health Services, North Adelaide; and the School of Paediatrics and Reproductive Medicine, University of Adelaide, Adelaide, Australia

The compound 4-hydroxynonenal (4-HNE) is the major aldehyde formed during lipid peroxidation of -6-polyunsaturated fatty acids and has been suggested to regulate inflammatory responses because it inhibits tumor necrosis factor (TNF) mRNA production in the human monocytic cell line THP-1. Here we demonstrate that 4-HNE inhibits TNF and interleukin-1β production in human monocytes in response to lipopolysaccharide. The main action of 4-HNE occurred at the pretranscriptional level; there was no effect on TNF mRNA production or stability when 4-HNE was added after stimulation. The mechanism of action of 4-HNE appears to be downstream of lipopolysaccharide-receptor binding. In the human monocytic MonoMac 6 cell line, 4-HNE caused selective inhibition of the activity of the mitogen-activated protein kinases p38 and ERK1/ERK2, but not JNK. However, in monocytes, the activities of all three kinases were inhibited, suggesting that the effects of 4-HNE were exerted at points upstream of ERK1/ERK2 and JNK as the levels of the phosphorylated kinases were reduced. In contrast, p38 phosphorylation was not inhibited, suggesting that 4-HNE affects kinase activity. 4-HNE also inhibited nuclear factor-B activation in monocytes. In view of the roles of p38, ERK1/ERK2, JNK, and nuclear factor-B in inflammation, the data suggest that 4-HNE, at nontoxic concentrations, has anti-inflammatory properties, most likely through an effect on these signaling molecules, and could lead to the development of novel treatments for inflammatory diseases.