Very long chain n‐3 and n‐6 polyunsaturated fatty acids inhibit proliferation of human T‐lymphocytes in vitro

Abstract

The effect of marine n-3 polyunsaturated fatty acids on proliferation of human T-cells in vitro was compared to other polyunsaturated, monounsaturated and saturated fatty acids. Monoenes and saturated fatty acids had little effect on T-cell proliferation. Eicosapentaenoic acid and docosahexaenoic acid exerted a strong dose-dependent inhibitory effect on proliferation of mitogen- or antigen-stimulated T-cells, similar to that observed for arachidonic acid. Sixty microM of albumin-bound eicosapentaenoic acid or arachidonic acid promoted 25-40% inhibition of proliferation of T-cells stimulated with mitogen, whereas the same concentration of albumin-bound docosahexaenoic acid promoted 60% inhibition. When epidermal cells (Langerhans cells) were used as antigen-presenting cells, 100 microM of albumin-bound eicosapentaenoic acid or arachidonic acid caused 40% inhibition on T-cell proliferation. Low density lipoprotein (LDL), isolated after four months of dietary intake of fish oil or corn oil, inhibited mitogen-stimulated T-cell proliferation in a dose-dependent manner. Fish oil- and corn oil-enriched LDL showed similar ability to inhibit T-cell proliferation. Epidermal cells preincubated with docosahexaenoic acid, and extensively washed before adding purified T-cells and antigen, resulted in a strong inhibition of T-cell proliferation, whereas preincubation of purified T-cells with docosahexaenoic acid did not cause any inhibitory effect. Cyclooxygenase and lipoxygenase inhibitors (indomethacin, acetylsalicylic acid, nordihydroguaertic acid) did not affect the antiproliferative effect of eicosapentaenoic acid and arachidonic acid, neither did the antioxidants butylated hydroxytoluene or alpha-tocopherol. Eicosanoids, (PGE2, PGE3, LTB4, LTB5 and lipoxin A or lipoxin B) added directly to mitogen-stimulated peripheral blood mononuclear cells (PBMC) did not influence T-cell proliferation significantly. Decreased viability was observed when mitogen-stimulated lymphocytes were cultured with essential polyunsaturated fatty acids, whereas the viability of unstimulated lymphocytes was hardly influenced by the same fatty acids. We conclude that; (a) pharmacological albumin-bound concentrations of the highly unsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid promote a strong antiproliferative effect on mitogen- and antigen-stimulated human T-cells: (b) docosahexaenoic acid can suppress accessory cell function and consequently suppress T-cell activation; (c) physiologic concentration of LDL particles rich in n-3 and n-6 fatty acids, both promote a dose-dependent antiproliferative effect on mitogen-stimulated PBMC; (d) the inhibition is independent of eicosanoid metabolites; and (e) lipid peroxidation seems unlikely to be responsible for the antiproliferative effect.

Multiplication and death-type of leukemia cell lines exposed to very long-chain polyunsaturated fatty acids

“…11,15 However, in two very similar reports, the addition of antioxidants together with PUFA had no reversible effect. 14,16 As none of these studies investigated if the reduced cell multiplication with PUFA was caused by apoptosis or necrosis, the discrepancies in these reports may be explained by our present findings. The conversion of AA and EPA to their respective eicosanoids has been proposed as an alternative mechanism for modulation of cancer cell multiplication.…”

“…12,13 Moreover, n-3 fatty acids and some other polyunsaturated fatty acids (PUFA) may decrease DNA synthesis and viability of cultured human lymphocytes. [14][15][16] It is not known whether effects of n-3 fatty acids on tumor size, metastasis, cell number or DNA synthesis are due to alterations in cell proliferation, cell differentiation or induction of the two main forms of cell death, necrosis and apoptosis. In a previous study on a promyelocytic leukemia cell line (HL-60), a reduced cell multiplication rate and DNA synthesis was observed after incubation with PUFA, and this was ascribed to effects on cell differentiation and cell viability.…”

Influence of Diets Containing Olive Oil, Sunflower Oil or Hydrogenated Coconut Oil on the Immune Response of Mice.

“…Previous studies have reported that diets containing oils or fatty acids added to the culture medium have strong effects on lymphocyte functions, in both animals and humans [1][2][3][4]. Polyunsaturated fatty acids (PUFA) such as (n-3) PUFA suppressed mitogen-stimulated proliferation of lymphocytes isolated from lymph nodes [ 1 ] and spleen of rats [ 5 ] , as well as from spleen of mice [ 5 ] and peripheral blood mononuclear cells from humans [4].…”

Effects of fatty acids and dietary lipids on cells of the immune system

“…Most studies agree that saturated fatty acids cause less inhibition than unsaturated fatty acids (Mertin & Hughes, 1975;Calder et al 1991Calder & Newsholme, 1992a,b;Soyland et al 1993;Rotondo et al 1994); there have been a number of reports of lack of inhibition by lauric and myristic acids (Weyman et al 1975Tsang et af. 1977;Calder et al 1991Calder & Newsholme, 1992a,b;Soyland et al 1993) and there appears to be general agreement that stearic acid is the most potent inhibitor of lymphocyte proliferation amongst the saturated fatty acids, causing a degree of inhibition similar to that of oleic acid (Calder et al 1991Calder & Newsholme, 1992a,b;Soyland et al 1993). Thus, amongst the saturated fatty acids the order of potencies appears to be:…”

“…1975Weyman et af. , 1977Tsang et al 1977;Buttke, 1984;Virella et al 1989;Calder et al 1990aCalder et al , 1991Calder & Newsholme, 1992a,b;Kumar et al 1992;Soyland et al 1993;Rotondo et al 1994). These studies show that oleic, linoleic, a-linolenic, y-linolenic, dihomo-y-linolenic, arachidonic, eicosapentaenoic and docosahexaenoic acids inhibit concanavalin A (Con A)-and/or phytohaemagglutinin (PHA)-stimulated proliferation of lymphocytes isolated from rodent lymphoid tissues (lymph nodes, spleen, thymus) and from human peripheral blood and have been reviewed in detail elsewhere (Yaqoob & Calder, 1993;.…”