Abstract
Results from our previous studies demonstrated that activation of Toll-like receptor 4 (Tlr4), the lipopolysaccharide (LPS) receptor, is sufficient to induce nuclear factor kappaB activation and expression of inducible cyclooxygenase (COX-2) in macrophages. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. Thus, we determined whether these fatty acids modulate LPS-induced signaling pathways and COX-2 expression in monocyte/macrophage cells (RAW 264.7). Results show that SFAs, but not unsaturated fatty acids (UFAs), induce nuclear factor kappaB activation and expression of COX-2 and other inflammatory markers. This induction is inhibited by a dominant-negative Tlr4. UFAs inhibit COX-2 expression induced by SFAs, constitutively active Tlr4, or LPS. However, UFAs fail to inhibit COX-2 expression induced by activation of signaling components downstream of Tlr4. Together, these results suggest that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Furthermore, these results suggest a possibility that propensity of monocyte/macrophage activation is modulated through Tlr4 by different types of free fatty acids, which in turn can be altered by kinds of dietary fat consumed.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma
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Animals
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Base Sequence
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Cell Line
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Colonic Neoplasms
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Consensus Sequence
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Cyclooxygenase 2
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Docosahexaenoic Acids / pharmacology
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Drosophila Proteins*
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Enzyme Induction / drug effects
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Fatty Acids, Nonesterified / pharmacology*
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Fatty Acids, Unsaturated / pharmacology*
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Gene Expression Regulation, Enzymologic / drug effects*
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Genes, Reporter
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Humans
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Isoenzymes / biosynthesis
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Isoenzymes / genetics*
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Lauric Acids / pharmacology
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Lipid A / pharmacology
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Lipopolysaccharides / pharmacology
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Macrophages
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Membrane Glycoproteins / drug effects
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Membrane Glycoproteins / physiology*
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Membrane Proteins
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Mice
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Monocytes
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NF-kappa B / metabolism
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type II
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Promoter Regions, Genetic
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Prostaglandin-Endoperoxide Synthases / biosynthesis
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Prostaglandin-Endoperoxide Synthases / genetics*
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Receptors, Cell Surface / drug effects
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Receptors, Cell Surface / physiology*
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Toll-Like Receptor 4
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Toll-Like Receptors
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Tumor Cells, Cultured
Substances
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Drosophila Proteins
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Fatty Acids, Nonesterified
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Fatty Acids, Unsaturated
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Isoenzymes
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Lauric Acids
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Lipid A
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Lipopolysaccharides
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Membrane Glycoproteins
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Membrane Proteins
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NF-kappa B
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Receptors, Cell Surface
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TLR4 protein, human
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Toll-Like Receptor 4
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Toll-Like Receptors
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lauric acid
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Docosahexaenoic Acids
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases