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Polyunsaturated fatty acid biosynthesis involving 8 desaturation and differential DNA methylation of FADS2 regulates proliferation of human peripheral blood mononuclear cells

Sibbons, Charlene, Irvine, N, Pérez-Mojica, J, Calder, P, Lillycrop, K, Fielding, Barbara and Burdge, G (2018) Polyunsaturated fatty acid biosynthesis involving 8 desaturation and differential DNA methylation of FADS2 regulates proliferation of human peripheral blood mononuclear cells Frontiers in Immunology, 9.

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Abstract

Polyunsaturated fatty acids (PUFAs) are important for immune function. Limited evidence indicates that immune cell activation involves endogenous PUFA synthesis, but this has not been characterised. To address this, we measured metabolism of 18:3n-3 in quiescent and activated peripheral blood mononuclear cells (PBMCs), and in Jurkat T cell leukaemia. PBMCs from men and women (n = 34) were incubated with [1-13C]18:3n-3 with or without Concanavalin A (Con. A). 18:3n-3 conversion was undetectable in unstimulated PBMCs, but up-regulated when stimulated. The main products were 20:3n-3 and 20:4n-3, while 18:4n-3 was undetectable, suggesting initial elongation and 8 desaturation. PUFA synthesis was 17.4-fold greater in Jurkat cells than PBMCs. The major products of 18:3n-3 conversion in Jurkat cells were 20:4n-3, 20:5n-3 and 22:5n-3. 13C Enrichment of 18:4n-3 and 20:3n-3 suggests parallel initial elongation and Δ6 desaturation. The FADS2 inhibitor SC26196 reduced PBMC, but not Jurkat cell, proliferation suggesting PUFA synthesis is involved in regulating mitosis in PBMCs. Con. A stimulation increased FADS2, FADS1, ELOVL5 and ELOVL4 mRNA expression in PBMCs. A single transcript corresponding to the major isoform of FADS2, FADS20001, was detected in PBMCs and Jurkat cells. PBMC activation induced hypermethylation of a 470bp region in the FADS2 5’-regulatory sequence. This region was hypomethylated in Jurkat cells compared to quiescent PBMCs. These findings show that PUFA synthesis involving initial elongation and 8 desaturation is involved in regulating PBMC proliferation and is regulated via transcription possibly by altered DNA methylation. These processes were dysregulated in Jurkat cells. This has implications for understanding the regulation of mitosis in normal and transformed lymphocytes.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Sibbons, Charlenec.sibbons@surrey.ac.uk
Irvine, N
Pérez-Mojica, J
Calder, P
Lillycrop, K
Fielding, BarbaraB.Fielding@surrey.ac.uk
Burdge, G
Date : 5 March 2018
Identification Number : 10.3389/fimmu.2018.00432
Copyright Disclaimer : Copyright 2018 Sibbons, Irvine, Pérez-Mojica, Calder, Lillycrop, Fielding and Burdge. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Uncontrolled Keywords : Peripheral blood mononuclear cells, polyunsaturated fatty acids, desaturase, elongase, DNA methylation, cell proliferation, transcription, leukaemia
Depositing User : Melanie Hughes
Date Deposited : 20 Feb 2018 11:37
Last Modified : 19 Jun 2018 09:41
URI: http://epubs.surrey.ac.uk/id/eprint/845866

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