BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Common and differential effects of docosahexaenoic acid and eicosapentaenoic acid on helper T-cell responses and associated pathways

  • Lee, Jaeho (Graduate Program of Science for Aging, Yonsei University) ;
  • Choi, Yu Ri (Graduate Program of Science for Aging, Yonsei University) ;
  • Kim, Miso (Graduate Program of Science for Aging, Yonsei University) ;
  • Park, Jung Mi (Department of Biostatistics and Computing, Graduate School of Yonsei University) ;
  • Kang, Moonjong (Department of Biostatistics and Computing, Graduate School of Yonsei University) ;
  • Oh, Jaewon (Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Lee, Chan Joo (Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Park, Sungha (Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kang, Seok-Min (Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Manabe, Ichiro (Department of Disease Biology and Molecular Medicine, Chiba University Graduate School of Medicine) ;
  • Ann, Soo-jin (Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Yonsei University College of Medicine) ;
  • Lee, Sang-Hak (Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine)
  • Received : 2020.12.06
  • Accepted : 2021.04.27
  • Published : 2021.05.31
Download PDF
⟨ Previous Next ⟩

Abstract

Our understanding of the differential effects between specific omega-3 fatty acids is incomplete. Here, we aimed to evaluate the effects of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on T-helper type 1 (Th1) cell responses and identify the pathways associated with these responses. Naïve CD4+ T cells were co-cultured with bone marrow-derived dendritic cells (DCs) in the presence or absence of palmitate (PA), DHA, or EPA. DHA or EPA treatment lowered the number of differentiated IFN-γ-positive cells and inhibited the secretion of IFN-γ, whereas only DHA increased IL-2 and reduced TNF-α secretion. There was reduced expression of MHC II on DCs after DHA or EPA treatment. In the DC-independent model, DHA and EPA reduced Th1 cell differentiation and lowered the cell number. DHA and EPA markedly inhibited IFN-γ secretion, while only EPA reduced TNF-α secretion. Microarray analysis identified pathways involved in inflammation, immunity, metabolism, and cell proliferation. Moreover, DHA and EPA inhibited Th1 cells through the regulation of diverse pathways and genes, including Igf1 and Cpt1a. Our results showed that DHA and EPA had largely comparable inhibitory effects on Th1 cell differentiation. However, each of the fatty acids also had distinct effects on specific cytokine secretion, particularly according to the presence of DCs.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea grant funded by the Korean government (grant numbers: 20181D1A1B07043855 and 2019R1F1A1057952). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References

  1. Bhatt DL, Steg PG, Miller M et al (2019) Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 380, 11-22 https://doi.org/10.1056/NEJMoa1812792
  2. Bhatt DL, Steg PG, Miller M et al (2019) Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J Am Coll Cardiol 74, 1159-1161 https://doi.org/10.1016/j.jacc.2019.06.043
  3. Kawashiri MA, Tada H, Yamagishi M (2018) Unsolved antiatherogenic mechanism of n-3 polyunsaturated fatty acids. Circ J 82, 332-333 https://doi.org/10.1253/circj.CJ-17-1252
  4. Son JW, Kim CH, Nam MS, Park IB, Yoo SJ (2019) Efficacy and safety of prescription of omega-3 fatty acids added to stable statin therapy in Korean patients with type 2 diabetes and hypertriglyceridemia: a randomized controlled trial. J Lipid Atheroscler 8, 221-231 https://doi.org/10.12997/jla.2019.8.2.221
  5. Gutierrez S, Svahn SL, Johansson ME (2019) Effects of omega-3 fatty acids on immune cells. Int J Mol Sci 20, 2476 https://doi.org/10.3390/ijms20102476
  6. Tabas I and Lichtman AH (2017) Monocyte-macrophages and T cells in atherosclerosis. Immunity 47, 621-634 https://doi.org/10.1016/j.immuni.2017.09.008
  7. Winkels H, Wolf D (2020) Heterogeneity of T cells in atherosclerosis defined by single-cell RNA-sequencing and cytometry by time of flight. Arterioscler Thromb Vasc Biol 41, 549-563 https://doi.org/10.1161/ATVBAHA.120.312137
  8. Tomas L, Bengtsson E, Andersson L et al (2020) Low levels of CD4 + CD28 null T cells at baseline are associated with first-time coronary events in a prospective population-based case-control cohort. Arterioscler Thromb Vasc Biol 40, 426-436 https://doi.org/10.1161/ATVBAHA.119.313032
  9. Duffney PF, Falsetta ML, Rackow AR, Thatcher TH, Phipps RP, Sime PJ (2018) Key roles for lipid mediators in the adaptive immune response. J Clin Invest 128, 2724-2731 https://doi.org/10.1172/JCI97951
  10. Cucchi D, Camacho-Munoz D, Certo M et al (2020) Omega-3 polyunsaturated fatty acids impinge on CD4+ T cell motility and adipose tissue distribution via direct and lipid mediator-dependent effects. Cardiovasc Res 116, 1006-1020
  11. Kong W, Yen JH, Vassiliou E, Adhikary S, Toscano MG, Ganea D (2010) Docosahexaenoic acid prevents dendritic cell maturation and in vitro and in vivo expression of the IL-12 cytokine family. Lipids Health Dis 9, 12 https://doi.org/10.1186/1476-511X-9-12
  12. Waickman AT, Powell JD (2012) mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev 249,43-58 https://doi.org/10.1111/j.1600-065X.2012.01152.x
  13. Chen Z, Zhang Y, Jia C et al (2014) mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression. Oncogene 33, 4548-4557 https://doi.org/10.1038/onc.2013.402
  14. Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E (2000) Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 101, 2149-2153 https://doi.org/10.1161/01.CIR.101.18.2149
  15. Yamagata K, Suzuki S, Tagami M (2016) Docosahexaenoic acid prevented tumor necrosis factor alpha-induced endothelial dysfunction and senescence. Prostaglandins Leukot. Essent Fatty Acids 104, 11-18 https://doi.org/10.1016/j.plefa.2015.10.006
  16. Albracht-Schulte K, Gonzalez S, Jackson A et al (2019) Eicosapentaenoic acid improves hepatic metabolism and reduces inflammation independent of obesity in high-fat-fed mice and in HepG2 cells. Nutrients 11, 599. https://doi.org/10.3390/nu11030599
  17. McMurray DN, Jolly CA, Chapkin RS (2000) Effects of dietary n-3 fatty acids on T cell activation and T cell receptor-mediated signaling in a murine model. J Infect Dis 182 Suppl 1, S103-107 https://doi.org/10.1086/315909
  18. Jolly CA, McMurray DN, Chapkin RS (1998) Effect of dietary n-3 fatty acids on interleukin-2 and interleukin-2 receptor alpha expression in activated murine lymphocytes. Prostaglandins Leukot. Essent Fatty Acids 58, 289-293 https://doi.org/10.1016/S0952-3278(98)90038-2
  19. Dietrich T, Hucko T, Schneemann C et al (2012) Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells. Atherosclerosis 220, 329-336 https://doi.org/10.1016/j.atherosclerosis.2011.09.050
  20. Hoppenbrouwers T, Cvejic Hogervorst JH, Garssen J, Wichers HJ, Willemsen LEM (2019) Long chain polyunsaturated fatty acids (LCPUFAs) in the prevention of food allergy. Front Immunol 10, 1118 https://doi.org/10.3389/fimmu.2019.01118
  21. Serhan CN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92-101 https://doi.org/10.1038/nature13479
  22. Chiurchiu V, Leuti A, Dalli J et al (2016) Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses. Sci Transl Med 8, 353ra111 https://doi.org/10.1126/scitranslmed.aaf7483
  23. Hua J, Jin Y, Chen Y et al (2014) The resolvin D1 analogue controls maturation of dendritic cells and suppresses alloimmunity in corneal transplantation. Invest Ophthalmol Vis Sci 55, 5944-5951 https://doi.org/10.1167/iovs.14-14356
  24. Kim W, Khan NA, McMurray DN, Prior IA, Wang N, Chapkin RS (2010) Regulatory activity of polyunsaturated fatty acids in T-cell signaling. Prog Lipid Res 49, 250-261 https://doi.org/10.1016/j.plipres.2010.01.002
  25. Fan YY, Fuentes NR, Hou TY et al (2018) Remodelling of primary human CD4+ T cell plasma membrane order by n-3 PUFA. Br J Nutr 119, 163-175 https://doi.org/10.1017/S0007114517003385
  26. Fan YY, Ly LH, Barhoumi R, McMurray DN, Chapkin RS (2004) Dietary docosahexaenoic acid suppresses T cell protein kinase C theta lipid raft recruitment and IL-2 production. J Immunol 173, 6151-6160 https://doi.org/10.4049/jimmunol.173.10.6151
  27. Mason RP, Jacob RF, Shrivastava S, Sherratt SCR, Chattopadhyay A (2016) Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta 1858, 3131-3140 https://doi.org/10.1016/j.bbamem.2016.10.002
  28. Yu XH, He LH, Gao JH, Zhang DW, Zheng XL, Tang CK (2018) Pregnancy-associated plasma protein-A in atherosclerosis: molecular marker, mechanistic insight, and therapeutic target. Atherosclerosis 278, 250-258 https://doi.org/10.1016/j.atherosclerosis.2018.10.004
  29. Sukhanov S, Higashi Y, Shai SY et al (2018) SM22α (smooth muscle protein 22-α) promoter-driven IGF1R (insulin-like growth factor 1 receptor) deficiency promotes atherosclerosis. Arterioscler Thromb Vasc Biol 38, 2306-2317 https://doi.org/10.1161/ATVBAHA.118.311134
  30. Higashi Y, Sukhanov S, Shai SY et al (2016) Insulin-like growth factor-1 receptor deficiency in macrophages accelerates atherosclerosis and induces an unstable plaque phenotype in apolipoprotein E-deficient mice. Circulation 133, 2263-2278 https://doi.org/10.1161/CIRCULATIONAHA.116.021805
  31. Clark R, Strasser J, McCabe S, Robbins K, Jardieu P (1993) Insulin-like growth factor-1 stimulation of lymphopoiesis. J Clin Invest 92, 540-548 https://doi.org/10.1172/JCI116621
  32. Bilbao D, Luciani L, Johannesson B, Piszczek A, Rosenthal N (2014) Insulin-like growth factor-1 stimulates regulatory T cells and suppresses autoimmune disease. EMBO Mol Med 6, 1423-1435 https://doi.org/10.15252/emmm.201303376
  33. Yoon IS, Park H, Kwak HW, Jung YW, Nam JH (2017) Macrophage-derived insulin-like growth factor-1 affects influenza vaccine efficacy through the regulation of immune cell homeostasis. Vaccine 35, 4687-4694 https://doi.org/10.1016/j.vaccine.2017.07.037
  34. Mashurabad PC, Kondaiah P, Palika R, Ghosh S, Nair MK, Raghu P (2016) Eicosapentaenoic acid inhibits intestinal β-carotene absorption by downregulation of lipid transporter expression via PPAR-α dependent mechanism. Arch Biochem Biophys 590, 118-124 https://doi.org/10.1016/j.abb.2015.11.002
  35. Nomura M, Liu J, Yu ZX et al (2019) Macrophage fatty acid oxidation inhibits atherosclerosis progression. J Mol Cell Cardiol 127, 270-276 https://doi.org/10.1016/j.yjmcc.2019.01.003
  36. Raud B, McGuire PJ, Jones RG, Sparwasser T, Berod L (2018) Fatty acid metabolism in CD8+ T cell memory: challenging current concepts. Immunol Rev 283, 213-231 https://doi.org/10.1111/imr.12655
  37. Patsoukis N, Bardhan K, Chatterjee P et al (2015) PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 6, 6692 https://doi.org/10.1038/ncomms7692