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Journal of Lipid Research, Vol 32, 1899-1910, Copyright © 1991 by Lipid Research, Inc.
LG Fong, TA Fong and AD Cooper
Recent studies have demonstrated the expression of messenger RNA (mRNA) for
several cytokines within atherosclerotic arteries. Since cytokines have
been shown to modulate functions of cultured arterial wall cells in a
manner that could influence atherogenesis, this suggests that factors that
modulate cytokine production would influence the atherosclerotic process.
To examine whether lipoproteins can modulate cytokine production, the
effect of lipoproteins on mouse macrophage interleukin-1 beta (IL-1 beta)
mRNA expression was examined by dot blot and Northern blot analyses. Low
density lipoprotein (LDL), acetylated- LDL, or malondialdehyde-LDL did not
induce IL-1 beta mRNA expression or affect the expression in response to
lipopolysaccharide (LPS). Similarly, copper ion-oxidized LDL did not
stimulate the production of IL-1 beta mRNA. However, oxidized LDL inhibited
the LPS-induced expression in a concentration- and time-dependent manner
with a maximum inhibition (greater than 90%) observed after a 2.5 h
preincubation with 25 micrograms protein/ml. These conditions did not
affect protein synthesis or phagocytosis and the inhibition was partially
reversible after 24 h, which together suggest that the inhibition was not
due to cell death. An inhibition of IL-1 alpha and IL-6 mRNA expression was
also observed while there was no change in gamma-actin mRNA levels. The
level of inhibition of IL-1 beta mRNA was dependent upon the extent of LDL
oxidation, but did not correlate with recognition by the scavenger
receptor. A non-receptor pathway was supported by two lines of evidence: 1)
the inhibition could be reproduced with a lipid extract, and 2) oxidized
LDL also inhibited scavenger receptor negative THP-1 cell IL-1 beta mRNA
expression. Finally, oxidized LDL had no effect on the turnover of IL-1
beta mRNA, suggesting that the decreased accumulation of IL-1 beta mRNA is
due to a decrease in gene transcription. Together these studies suggest
that as macrophages become foam cells their immune responsiveness is
attenuated.
ARTICLES
Inhibition of lipopolysaccharide-induced interleukin-1 beta mRNA expression in mouse macrophages by oxidized low density lipoprotein
Research Institute, Palo Alto Medical Foundation, CA 94301.
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