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Type: Journal article
Title: 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
Author: Marantos, C.
Mukaro, V.
Ferrante, J.
Hii, C.
Ferrante, A.
Citation: American Journal of Pathology, 2008; 173(4):1057-1066
Publisher: Amer Soc Investigative Pathology Inc
Issue Date: 2008
ISSN: 0002-9440
Statement of
Christos Marantos, Violet Mukaro, Judith Ferrante, Charles Hii, and Antonio Ferrante
Abstract: The compound 4-hydroxynonenal (4-HNE) is the major aldehyde formed during lipid peroxidation of omega-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-1beta 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-kappaB activation in monocytes. In view of the roles of p38, ERK1/ERK2, JNK, and nuclear factor-kappaB 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.
Keywords: Monocytes; Cell Line; Macrophages; Humans; Aldehydes; Mitogen-Activated Protein Kinases; Extracellular Signal-Regulated MAP Kinases; JNK Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Lipopolysaccharides; Fatty Acids, Omega-6; Tumor Necrosis Factor-alpha; NF-kappa B; Transcription, Genetic; Protein Processing, Post-Translational; Enzyme Activation; RNA Stability; Oxidation-Reduction; Phosphorylation; I-kappa B Proteins; Interleukin-1beta; NF-KappaB Inhibitor alpha
Description: Copyright © 2008 American Society for Investigative Pathology
RMID: 0020082738
DOI: 10.2353/ajpath.2008.071150
Appears in Collections:Paediatrics publications

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