Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4

J Biol Chem. 2001 May 18;276(20):16683-9. doi: 10.1074/jbc.M011695200. Epub 2001 Mar 2.


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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma
  • Animals
  • Base Sequence
  • Cell Line
  • Colonic Neoplasms
  • Consensus Sequence
  • Cyclooxygenase 2
  • Docosahexaenoic Acids / pharmacology
  • Drosophila Proteins*
  • Enzyme Induction / drug effects
  • Fatty Acids, Nonesterified / pharmacology*
  • Fatty Acids, Unsaturated / pharmacology*
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Genes, Reporter
  • Humans
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics*
  • Lauric Acids / pharmacology
  • Lipid A / pharmacology
  • Lipopolysaccharides / pharmacology
  • Macrophages
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / physiology*
  • Membrane Proteins
  • Mice
  • Monocytes
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Promoter Regions, Genetic
  • Prostaglandin-Endoperoxide Synthases / biosynthesis
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / physiology*
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Cells, Cultured


  • Drosophila Proteins
  • Fatty Acids, Nonesterified
  • Fatty Acids, Unsaturated
  • Isoenzymes
  • Lauric Acids
  • Lipid A
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Membrane Proteins
  • NF-kappa B
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • lauric acid
  • Docosahexaenoic Acids
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases