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https://hdl.handle.net/2440/50868
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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 1525-2191 |
Statement of Responsibility: | 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 |
DOI: | 10.2353/ajpath.2008.071150 |
Grant ID: | NHMRC |
Published version: | http://dx.doi.org/10.2353/ajpath.2008.071150 |
Appears in Collections: | Aurora harvest 5 Paediatrics publications |
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