Research Article
Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids

https://doi.org/10.1194/jlr.M200361-JLR200Get rights and content
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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 NFκB 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.

unsaturated and saturated fatty acids
n-3 polyunsaturated fatty acids
Toll-like receptors
NFκB
cyclooxygenase-2

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    Abbreviations

    AA

    arachidonic acid

    COX

    cyclooxygenase

    DHA

    docosahexaenoic acid

    EPA

    eicosapentaenoic acid

    LA

    linoleic acid

    LPS

    lipopolysaccharide

    NFκB

    nuclear factor κB

    MyD88

    myeloid differential factor 88

    NIK

    NFκB-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