Abstract
n-3 polyunsaturated fatty acids (PUFA) influences a variety of disease conditions, such as hypertension, heart disease, diabetes, cancer and allergic diseases, by modulating membrane constitution, inhibiting production of proinflammatory eicosanoids and cytokines, and binding to cell surface and nuclear receptors. We have previously shown that n-3 PUFA inhibit mast cell functions by disrupting high affinity IgE receptor (FcεRI) lipid raft partitioning and subsequent suppression of FcεRI signaling in mouse bone marrow-derived mast cells. However, it is still largely unknown how n-3 PUFA modulate human mast cell function, which could be attributed to multiple mechanisms. Using a human mast cell line (LAD2), we have shown similar modulating effects of n-3 PUFA on FcεRI lipid raft shuttling, FcεRI signaling, and mediator release after cell activation through FcεRI. We have further shown that these effects are at least partially associated with ligation of G protein-coupled receptor 120 expressed on LAD2 cells. This observation has advanced our mechanistic knowledge of n-3 PUFA's effect on mast cells and demonstrated the interplay between n-3 PUFA, lipid rafts, FcεRI, and G protein-coupled receptor 120. Future research in this direction may present new targets for nutritional intervention and therapeutic agents.
Highlights
As precursors of eicosanoids and important constituents of lipid membranes, n-3 polyunsaturated fatty acids (PUFA) especially eicosapentaenoic acid (EPA, 20:5, n-3) and docosahexaenoic acid (DHA, 22:6, n-3) have significant impacts on inflammatory diseases. n-3 PUFA may play important roles in various diseases such as rheumatoid arthritis, inflammatory bowel disease, asthma, cancer, diabetes, cardiovascular disease, neurodegenerative disease, hyperlipidemia, and hypertension n-3 PUFA Modify FcεRI Signaling [1,2,3,4,5,6,7]
One of the major beneficial properties of n-3 PUFA is their action as anti-inflammatory molecules [12]. n-3 PUFA reduce the production of pro-inflammatory mediators by competitively inhibiting the synthesis of eicosanoids from arachidonic acid (AA, 20:4, n-6) and suppressing the gene transcription of pro-inflammatory cytokines through binding to cell surface G protein-coupled receptor (GPR) 40 and G Protein-Coupled Receptor 120 (GPR120), called free fatty acid receptors 1 and 4 (FFA1 and FFA4), as well as nuclear peroxisome proliferator-activated receptors (PPAR) [2]
Since n-PUFA are known to activate GPR40 and GPR120, we examined the role of these receptors in mast cell degranulation, showing for the first time that these receptors are expressed by human mast cells and have a functional role in mast cell mediator release
Summary
As precursors of eicosanoids and important constituents of lipid membranes, n-3 polyunsaturated fatty acids (PUFA) especially eicosapentaenoic acid (EPA, 20:5, n-3) and docosahexaenoic acid (DHA, 22:6, n-3) have significant impacts on inflammatory diseases. n-3 PUFA may play important roles in various diseases such as rheumatoid arthritis, inflammatory bowel disease, asthma, cancer, diabetes, cardiovascular disease, neurodegenerative disease, hyperlipidemia, and hypertension n-3 PUFA Modify FcεRI Signaling [1,2,3,4,5,6,7]. Previous work from our lab suggests that n-3 PUFA modulate the response of prostate cancer cells to interferon-γ and inhibit the production of interleukin-18 binding protein, which neutralizes interleukin-18 [13] Both EPA and DHA can be metabolized to produce anti-inflammatory molecules called resolvins and protectins, capable of dampening inflammation [12, 14]. Our previous study using mouse bone marrow-derived mast cells suggests that n-3 PUFA inhibit mast cell activation by suppressing FcεRImediated signal transduction and disrupting FcεRI shuttling to lipid rafts, which are specialized membrane microdomains with concentrated localization of transmembrane proteins, sphingolipids, and cholesterol [23]. FcεRI-mediated phosphorylation of downstream signaling molecules such as the spleen tyrosine kinase (Syk) and linker for activated T cells (LAT) Disruption of this membraneproximal event thereby leads to dampened degranulation and cytokine release. Since n-PUFA are known to activate GPR40 and GPR120, we examined the role of these receptors in mast cell degranulation, showing for the first time that these receptors are expressed by human mast cells and have a functional role in mast cell mediator release
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