Functional role of lipid metabolism in activated T-lymphocytes

Goppelt, Margarete; Köhler, Lars; Resch, Klaus

doi:10.1016/0005-2760(85)90104-3

Cited by 33 publications

(17 citation statements)

References 20 publications

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“…While OA and LA are found primarily in the PC fraction, AA is transferred to both PE and PI. Several groups have reported a redistribution of AA from PC to PE when AA was provided to cells (Aeberhard et al, 1984;Goppelt et al, 1985). We observed that the 36B 10 cells rapidly converted the GLA supplied to AA; the transfer of radioactivity from the PC to the PE fraction may reflect this conversion of GLA to AA.…”

Section: Discussionmentioning

confidence: 51%

γ-Linolenic acid (GLA) is cytotoxic to 36B10 malignant rat astrocytoma cells but not to 'normal' rat astrocytes

Vartak

McCaw²,

Davis³

et al. 1998

Br J Cancer

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Summary This study compares the effect of y-linolenic acid (GLA) and its precursor linoleic acid (LA) on survival of 36B10 malignant rat astrocytoma cells and 'normal' rat astrocytes. GLA was cytotoxic to 36B10 cells but not to astrocytes. By contrast, LA supplementation did not affect the survival of either cell types. There were minor differences in the uptake, distribution and use of radiolabelled GLA and LA by the 36B1 0 cells and astrocytes. GLA and LA supplementation increased the total polyunsaturated fatty acid (PUFA) content of the cells indicating increased oxidative potential. However, elevated levels of 8-isoprostane, an indicator of increased oxidative stress, were only observed in the GLA supplemented 36B10 cells. Addition of the antioxidant trolox to GLA-enriched 36B10 cells blocked the cytotoxic effect. Further, GLA enhanced the radiation sensitivity of the astrocytoma cells but not the astrocytes; trolox blocked the GLA-mediated increase in astrocytoma cell radiosensitivity. LA did not affect the radiation response of either cell type. While cyclo-oxygenase inhibitors did not affect GLA cytotoxicity, they blocked the enhanced radiation response of GLA-supplemented cells. The lipoxygenase inhibitor NDGA did not affect the toxicity produced by GLA. Thus, GLA is toxic to the neoplastic astrocytoma cells but not to normal astrocytes.Keywords: polyunsaturated fatty acids; y-linolenic acid; linoleic acid; astrocytoma; astrocyte; radiation Gamma linolenic acid (GLA, 18:3n6) supplementation has been reported to suppress the growth of tumour cells in vitro (Fujiwara et al, 1986;Sangeetha and Das, 1992;Falconer et al, 1994) and in vivo (Karmali et al, 1985;Abou et al, 1987). Interestingly, in separate studies conducted on normal tissues in vivo, it has been reported that dietary GLA decreases the severity of radiation damage to the skin (Hopewell et al, 1993) and CNS (Hopewell et al, 1994). We have previously shown that GLA supplementation can decrease clonogenic cell survival of malignant rat astrocytoma cells and increase their radiosensitivity (Vartak et al, 1997). To determine the therapeutic potential of this observation, it is important to investigate the effect of GLA on 'normal' rat astrocytes. The purpose of this work was to compare the effects of GLA on the survival of 36B10 astrocytoma cells and astrocytes and their response to radiation. The uptake and use of GLA by astrocytoma cells has also been compared with that by astrocytes.The cytotoxic action of polyunsaturated fatty acids (PUFAs) is thought to be mediated predominantly via lipid peroxidation and free radical generation (Begin et al, 1988;Ells et al, 1996). Several studies also indicate that eicosanoid and leukotriene synthesis play an important role in tumour cell proliferation and metastasis (Earashi et al, 1995; Damtew and Spagnuolo, 1997). Arachidonic acid (AA, 20:4n6) and dihomo-y-linolenic acid (DGLA, 20:3n6) are the substrate for the biosynthesis of prostaglandins of the 2-and 1-series respectively (Crawford, 1983 Bell JG et ...

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Section: Discussionmentioning

confidence: 51%

γ-Linolenic acid (GLA) is cytotoxic to 36B10 malignant rat astrocytoma cells but not to 'normal' rat astrocytes

Vartak

McCaw²,

Davis³

et al. 1998

Br J Cancer

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“…Fig. 4 shows one representative of three studies where treatment with either AAOCF 3 or BEL caused a concentration-dependent inhibition of PHA-induced proliferation. Pretreatment with the 14-kDa PLA 2 inhibitor, SB203347, however, had no effect on lymphocyte proliferation induced by PHA.…”

Section: Effect Of Phospholipase a 2 Inhibitors On Jurkat T Cell And mentioning

confidence: 99%

“…More specifically, mitogen activation of lymphocytes is accompanied by an increase in fatty acid turnover and an enrichment of PL with AA, the major substrate of proinflammatory eicosanoids (3)(4)(5)(6). The AA comes from internal pools since the enrichment occurs in serum-free conditions (3,4). The fact that this phenomenon, requiring deacylation-reacylation of PL, is AA specific and targeted toward selected PL classes (e.g.…”

mentioning

confidence: 99%

“…Preparation for cell division requires not only synthesis of nucleotide pools and new protein but also increases in phospholipid (PL) 1 content and remodeling of existing PL in support of new membrane formation (1). Several studies have demonstrated that changes in membrane PL (1, 2) and arachidonic acid (AA) metabolism (3,4) occur during the cell cycle. More specifically, mitogen activation of lymphocytes is accompanied by an increase in fatty acid turnover and an enrichment of PL with AA, the major substrate of proinflammatory eicosanoids (3)(4)(5)(6).…”

mentioning

confidence: 99%

“…Several studies have demonstrated that changes in membrane PL (1, 2) and arachidonic acid (AA) metabolism (3,4) occur during the cell cycle. More specifically, mitogen activation of lymphocytes is accompanied by an increase in fatty acid turnover and an enrichment of PL with AA, the major substrate of proinflammatory eicosanoids (3)(4)(5)(6). The AA comes from internal pools since the enrichment occurs in serum-free conditions (3,4).…”

mentioning

confidence: 99%

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Human Calcium-independent Phospholipase A2 Mediates Lymphocyte Proliferation

Roshak

Capper

Stevenson

et al. 2000

Journal of Biological Chemistry

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Activation of lymphocytes induces blastogenesis and cell division which is accompanied by membrane lipid metabolism such as increased fatty acid turnover. To date little is known about the enzymatic mechanism(s) regulating this process. Release of fatty acids such as arachidonic acid requires sn-2-deacylation catalyzed by a class of enzymes known as phospholipases A 2 (PLA 2 , EC 3.1.1.4). Herein, we confirm that human peripheral blood B or T lymphocytes (PBL) do not possess measurable levels of 85-kDa PLA 2 as assessed by Western immunoblot. Low levels of 14-kDa PLA 2 protein and activity were detectable in the particulate fraction of PBL and Jurkat cells. Western immunoblot analysis indicates that PBLs possess the calcium-independent PLA 2 (iPLA 2 ) protein. Calcium-independent sn-2-acylhydrolytic activity was measurable in PBL cytosols and could be inhibited by the selective iPLA 2 inhibitor bromoenol lactone. Mitogen activation of PBLs resulted in maintenance of activity levels which remained constant over 72 h suggesting an important role for iPLA 2 in this proliferative process. Indeed, evaluation of iPLA 2 activity in cell cycle-arrested Jurkat T cell fractions revealed the highest iPLA 2 levels occurring at the G 2 /M phase. Addition of the iPLA 2 inhibitors, bromoenol lactone, or arachidonyl trifluoromethyl ketone (AAOCF 3 ), inhibited both mitogen-induced PBL as well as Jurkat T cell proliferation. Moreover, specific depletion of iPLA 2 protein by antisense treatment also resulted in marked suppression of cell division. Inhibition of Jurkat cell proliferation was not associated with arrest at a particular phase of the cell cycle nor was it associated with apoptosis as assessed by flow cytometry. These findings provide the first evidence that iPLA 2 plays a key role in the lymphocyte proliferative response.Activation of resting lymphocytes occurs by ligation of antigen-specific co-receptors or artificially through mitogen stimulation. This in turn results in the formation of blast cells which undergo cellular proliferation, differentiation, and clonal expansion. Preparation for cell division requires not only synthesis of nucleotide pools and new protein but also increases in phospholipid (PL) 1 content and remodeling of existing PL in support of new membrane formation (1). Several studies have demonstrated that changes in membrane PL (1, 2) and arachidonic acid (AA) metabolism (3, 4) occur during the cell cycle. More specifically, mitogen activation of lymphocytes is accompanied by an increase in fatty acid turnover and an enrichment of PL with AA, the major substrate of proinflammatory eicosanoids (3-6). The AA comes from internal pools since the enrichment occurs in serum-free conditions (3, 4). The fact that this phenomenon, requiring deacylation-reacylation of PL, is AA specific and targeted toward selected PL classes (e.g. phosphatidylethanolamine and phosphatidylinositol) suggests regulation through specific enzyme systems (4). Indeed, the lysophosphatide acyltransferase, a reacylating enzyme, pr...

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Endocytosis of three serum proteins of a multigene family and of arachidonic acid in human lectin‐stimulated T lymphocytes

Geuskens

Torres

Estéban

et al. 1994

Microscopy Res & Technique

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Alpha-fetoprotein (AFP), serum albumin (SA), and vitamin D binding protein (DBP) are members of a multigene family of proteins showing high structural homology. AFP and SA exhibit a reciprocal relation during development and carry mostly fatty acids, while DBP carries vitamin D and its metabolites in the plasma. Covalent conjugates of these proteins with horseradish peroxidase (HRP) were used to follow by cytochemistry, at the electron microscope level, the protein uptake and intracellular pathways in peripheral blood human lymphocytes stimulated to blast formation by phytohemagglutinin (PHA). Transferrin (Tf), an iron-binding plasma protein, was used as a control. Combined with the results of competition and saturability experiments reported elsewhere, the ultrastructural observations are in favour of a specific endocytosis of the four proteins through cell surface receptors. Tf and AFP enter the cells via small vesicles and endosomes and move to multivesicular bodies (MVBs) and tubular vesicular elements located in the Golgi-centrosphere region to be finally recycled back into the medium. A noncovalent conjugate of AFP-HRP with 3H arachidonic acid [3H-(20:4)] is strongly internalized at 37 degrees C in PHA-stimulated lymphocytes; the autoradiographic labelling, localized in cellular membranes and mostly in lipid droplets, was only occasionally associated with organelles where the presence of AFP-HRP was cytochemically detected. SA, which competes with AFP for a common binding site on the surface of activated T cells, is endocytosed through small vesicles, endosomes, and MVBs before being released in a degraded form from the cells, in agreement with the localization of SA-HRP in lysosome-like organelles. DBP-HRP is poorly internalized through noncoated vesicles, endosomes, and MVBs and is finally routed to lysosomes. The physiological role of AFP and SA would be to mediate the transfer of fatty acids into cells, while that of DBP would be to facilitate the intracellular delivery of vitamin D.

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Functional role of lipid metabolism in activated T-lymphocytes

Cited by 33 publications

References 20 publications

γ-Linolenic acid (GLA) is cytotoxic to 36B10 malignant rat astrocytoma cells but not to 'normal' rat astrocytes

γ-Linolenic acid (GLA) is cytotoxic to 36B10 malignant rat astrocytoma cells but not to 'normal' rat astrocytes

Human Calcium-independent Phospholipase A2 Mediates Lymphocyte Proliferation

Endocytosis of three serum proteins of a multigene family and of arachidonic acid in human lectin‐stimulated T lymphocytes

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