Saturated and Polyunsaturated Fatty Acids Reciprocally Modulate Dendritic Cell Functions Mediated through TLR4

Abstract

TLRs provide critical signals to induce innate immune responses in APCs such as dendritic cells (DCs) that in turn link to adaptive immune responses. Results from our previous studies demonstrated that saturated fatty acids activate TLRs, whereas n-3 polyunsaturated fatty acids inhibit agonist-induced TLR activation. These results raise a significant question as to whether fatty acids differentially modulate immune responses mediated through TLR activation. The results presented in this study demonstrate that the saturated fatty acid, lauric acid, up-regulates the expression of costimulatory molecules (CD40, CD80, and CD86), MHC class II, and cytokines (IL-12p70 and IL-6) in bone marrow-derived DCs. The dominant negative mutant of TLR4 or its downstream signaling components inhibits lauric acid-induced expression of a CD86 promoter-reporter gene. In contrast, an n-3 polyunsaturated fatty acid, docosahexaenoic acid, inhibits TLR4 agonist (LPS)-induced up-regulation of the costimulatory molecules, MHC class II, and cytokine production. Similarly, DCs treated with lauric acid show increased T cell activation capacity, whereas docosahexaenoic acid inhibits T cell activation induced by LPS-treated DCs. Together, our results demonstrate that the reciprocal modulation of both innate and adaptive immune responses by saturated fatty acid and n-3 polyunsaturated fatty acid is mediated at least in part through TLRs. These results imply that TLRs are involved in sterile inflammation and immune responses induced by nonmicrobial endogenous molecules. These results shed new light in understanding how types of dietary fatty acids differentially modulate immune responses that could alter the risk of many chronic diseases.

Downregulation of genes involved in NFκB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: the GENOBIN study

“…Dietary components and exercise can also play a role in S I and possibly in TLR4 and CCL5 [6,8,[41][42][43][44][45][46][47]. This study is too small to reliably assess the independent effect of physical activity and diet, but adjustment for changes in physical activity frequency, serum NEFA and energy-adjusted intake of total fat, saturated fat, monounsaturated fat, polyunsaturated fat or total fibre did not attenuate the independent effect of changes in waist circumference and TLR4, TLR2, TNFRSF1A or CCL5 on changes in S I (data not shown).…”

Palmitate and Lipopolysaccharide Trigger Synergistic Ceramide Production in Primary Macrophages

“…Yet dysregulation of their expression and release has been linked to excessive tissue damage and the development of insulin resistance and diabetes (28,30,41). Although it has been suggested that fatty acids can directly activate TLRs, leading to the production of cytokines, this notion is still controversial given the presence of contaminants in many BSA preparations (3,42,43). Using ultrapure BSA we observed that palmitate-treated macrophages did not release IL-1␤ or TNF␣ even through the combination of palmitate and LPS significantly stimulated the release of these cytokines.…”

Long-chain fatty acids and inflammation

“…The effects of n-3 PUFA have been shown to involve inhibition of LPS-induced activation of NF-kB associated with decreased IkB phosphorylation (4,24) . In contrast, SFA, especially lauric acid, enhanced NF-kB activation in macrophages (4) and dendritic cells (5) and so promoted inflammatory gene expression. Lee et al (4) found that EPA and DHA, as well as other unsaturated fatty acids (arachidonic, linoleic and oleic acids), were able to prevent the pro-inflammatory effect of lauric acid in macrophages.…”

“…With regard to inflammation it is often considered that it is the PUFA of the n-6 and n-3 families that are most important, these often acting to oppose one another's actions (3) . However, it is now recognised that other fatty acids and fatty acid families are likely also involved in inflammation, with fairly recent work focusing on SFA (4)(5)(6) . There are a number of general mechanisms by which fatty acid exposures could affect inflammatory cell function, and so inflammatory processes.…”

“…Bacterial lipopolysaccharide (LPS), which is also known as endotoxin, induces inflammation by activating NF-kB, as do some inflammatory cytokines and UV irradiation. Cell culture studies with the n-3 PUFA EPA and DHA show inhibition of LPSinduced production of COX-2, inducible NO synthase, TNFa, IL-1, IL-6, IL-8 and IL-12 in endothelial cells (10,11) , monocytes (12,13) , macrophages (4) and dendritic dells (5,14) . Animal feeding studies with fish oil, a source of EPA and DHA, support the observations made in vitro with respect to the effects of n-3 PUFA on inflammatory cytokine production.…”