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

Abstract

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-1␤ 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 antiinflammatory properties, most likely through an effect on these signaling molecules, and could lead to the development of novel treatments for inflammatory diseases.

Regulation of CRIg Expression and Phagocytosis in Human Macrophages by Arachidonate, Dexamethasone, and Cytokines

“…On the other hand, others have shown that cross-linking of CRIg (or Z39Ig) on human monocytic THP-1 cells causes nuclear translocation of nuclear factor-B and increases expression of matrix metallopeptidase-9 and secretion of IL-8, and that PMA treatment of the human myeloid leukemia cell line TF-1A resulted in increased expression of CRIg. 30 Apart from the substantial differences that exist between normal macrophages and macrophage cell lines, 10 these data are consistent with activation of macrophages via CRIg as crucial for the clearance of complement opsonized microbial pathogens in the absence of a cytokine storm.…”

“…Monocytes were purified from PBMCs by density gradient centrifugation, as described previously. 9,10 Briefly, PBMCs were washed with RPMI-FCS containing 1 mmol/L EDTA at room temperature. Cells were layered on a 46% iso-osmotic Percoll gradient (GE Healthcare) and spun at 600 ϫ g for 30 minutes at room temperature.…”

Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2

“…Both pro-and anti-infl ammatory activities have been ascribed to glycerophospholipids harboring fragmented and/or oxidized sn -2 fatty acyl groups (59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69). Similarly, lyso-PC ( 66,(70)(71)(72)(73)(74) ) and short and/or oxidized fatty acids (75)(76)(77)(78)(79)(80) have been reported to elicit both detrimental and benefi cial responses. In general, in vitro approaches are strategically useful initially, but they have the usual limitations of studies that do not recapitulate essential in vivo features.…”

Protein Kinase Cα Regulates the Expression of Complement Receptor Ig in Human Monocyte–Derived Macrophages

“…LPS was added to cells at 10 ng/ml final concentration (21). The plate was incubated in 37˚C for 24 h, and the supernatants were harvested for cytokine measurements.…”