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.
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.
Marantos
Christos
C
The Sansom Institute and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
Mukaro
Violet
V
Ferrante
Judith
J
Hii
Charles
C
Ferrante
Antonio
A
D000447:Aldehydes / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D043371:Fatty Acids, Omega-6 / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000447:Aldehydes; D043371:Fatty Acids, Omega-6; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal
J Clin Invest. 1997 Mar 15;99(6):1445-52
9077554
FEBS Lett. 1996 Jun 17;388(2-3):119-22
8690068
J Clin Invest. 1998 Dec 1;102(11):1942-50
9835619
J Immunol Methods. 1978;24(3-4):389-93
722104
Bioorg Med Chem Lett. 2001 Nov 5;11(21):2867-70
11597418
Biochem J. 1994 Nov 15;304 ( Pt 1):87-94
7998962
Chem Biol Interact. 2001 Jan 30;130-132(1-3):943-54
11306108
Free Radic Biol Med. 2002 Oct 1;33(7):974
12361807
J Immunol Methods. 2004 May;288(1-2):123-34
15183091
Free Radic Biol Med. 2007 Mar 1;42(5):654-64
17291989
Arthritis Res. 2001;3(1):18-26
11178124
J Biol Chem. 1996 Feb 23;271(8):4138-42
8626753
FEBS Lett. 1996 Jun 17;388(2-3):165-8
8690078
Biochim Biophys Acta. 1984 Feb 9;792(2):172-81
6320898
Pharmacol Ther. 2003 Nov;100(2):171-94
14609719
Chem Res Toxicol. 2004 Jul;17(7):937-41
15257619
Rapid Commun Mass Spectrom. 2005;19(6):849-58
15723435
Biochim Biophys Acta. 1986 Mar 21;876(1):154-66
3081043
J Immunol. 1998 Nov 15;161(10):5681-6
9820549
J Biol Chem. 1998 Jul 24;273(30):19277-82
9668117
Prog Lipid Res. 2003 Jul;42(4):318-43
12689622
J Biol Chem. 1999 Apr 23;274(17):11611-8
10206970
J Leukoc Biol. 2001 Jan;69(1):3-10
11200064
J Immunol. 2003 Jul 15;171(2):628-35
12847227
Cell Signal. 2001 Feb;13(2):85-94
11257452
Rev Physiol Biochem Pharmacol. 1996;127:31-64
8533011
Hepatology. 1999 May;29(5):1565-72
10216144
J Pharmacol Exp Ther. 2008 Jan;324(1):306-12
17921189
J Leukoc Biol. 2002 Feb;71(2):339-47
11818456
Arch Biochem Biophys. 2002 Jan 15;397(2):240-5
11795877
Mol Aspects Med. 2003 Aug-Oct;24(4-5):167-75
12892994
Free Radic Biol Med. 2005 Feb 15;38(4):463-71
15649648
Adv Immunol. 1988;42:213-31
2834923
J Biol Chem. 2004 Nov 12;279(46):48389-96
15355999
Circ Res. 2006 Jul 7;99(1):34-41
16763165
J Immunol. 2005 Mar 15;174(6):3169-72
15749845
J Biol Chem. 2005 Mar 4;280(9):8617-27
15611045
FASEB J. 1997 Sep;11(11):851-7
9285483
Free Radic Biol Med. 1991;11(1):81-128
1937131
Biochem Biophys Res Commun. 2002 Jun 14;294(3):547-52
12056801
J Lipid Res. 2003 May;44(5):917-26
12588949
Biochem Biophys Res Commun. 2001 Mar 30;282(2):557-61
11401496
Immunology. 2004 Oct;113(2):153-62
15379975
Infect Immun. 1990 Dec;58(12):3996-4003
2254024
J Pharm Pharmacol. 1997 Feb;49(2):150-3
9055186