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Journal of Lipid Research, Vol. 44, 479-486, March 2003
Copyright © 2003 by Lipid Research, Inc.

Differential modulation of Toll-like receptors by fatty acids

Joo Y. Lee, Anthony Plakidas, Won H. Lee, Anne Heikkinen, Prithiva Chanmugam, George Bray and Daniel H. Hwang¹

Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808

¹ To whom correspondence should be addressed. e-mail: dhwang{at}whnrc.usda.gov

Human subjects consuming fish oil showed a significant suppression of cyclooxygenase-2 (COX-2) expression in blood monocytes when stimulated in vitro with lipopolysaccharide (LPS), an agonist for Toll-like receptor 4 (TLR4). Results with a murine monocytic cell line (RAW 264.7) stably transfected with COX-2 promoter reporter gene also demonstrated that LPS-induced COX-2 expression was preferentially inhibited by docosahexaenoic acid (DHA, C22:6n-3) and eicosapentaenoic acid (EPA, C20:5n-3), the major n-3 polyunsaturated fatty acids (PUFAs) present in fish oil. Additionally, DHA and EPA significantly suppressed COX-2 expression induced by a synthetic lipopeptide, a TLR2 agonist. These results correlated with the preferential suppression of LPS- or lipopeptide-induced NFB activation by DHA and EPA. The target of inhibition by DHA is TLR itself or its associated molecules, but not downstream signaling components. In contrast, COX-2 expression by TLR2 or TRL4 agonist was potentiated by lauric acid, a saturated fatty acid. These results demonstrate that inhibition of COX-2 expression by n-3 PUFAs is mediated through the modulation of TLR-mediated signaling pathways.

Thus, the beneficial or detrimental effects of different types of dietary fatty acids on the risk of the development of many chonic inflammatory diseases may be in part mediated through the modulation of TLRs.

Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LA, linoleic acid; LPS, lipopolysaccharide; NFB, nuclear factor B; MyD88, myeloid differential factor 88; NIK, NFB-inducing kinase; OA, oleic acid; PamCAG, palmitoyl-Cys((RS)-2,3-di(palmitoyloxy)-propyl)-Ala-Gly-OH; PUFA, polyunsaturated fatty acid; TLR, Toll-like receptors

Supplementary key words unsaturated and saturated fatty acids • n-3 polyunsaturated fatty acids • Toll-like receptors • NFB • cyclooxygenase-2

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