Modulation of the expression of cyclooxygenase-2 by fatty acids mediated through toll-like receptor 4-derived signaling pathways.
Genetic evidence that Toll-like receptor 4 (Tlr4) is the lipopolysaccharide (LPS) receptor and biochemical evidence that Tlr4 confers LPS responsiveness as determined by activation of NF-kappaB and expression of inducible cyclooxygenase 2 have been demonstrated. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. It is now demonstrated that SFAs, but not unsaturated fatty acids (UFAs), induce NF-kappaB activation and expression of COX-2 and other inflammatory markers in macrophages. UFAs inhibit COX-2 expression induced by SFAs and LPS. Additional evidence suggests 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. Whether fatty acids also modulate signaling pathways and target gene expression derived from the activation of other Tlrs remains to be determined.-Hwang, D. Modulation of the expression of cyclooxygenase 2 by fatty acids mediated through Toll-like receptor 4-derived signaling pathways.
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Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808, USA. hwangdh@pbrc.edu
D000818:Animals; D051546:Cyclooxygenase 2; D029721:Drosophila Proteins; D005227:Fatty Acids / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D005227:Fatty Acids; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases