Showing papers by "Philip C. Calder published in 1998"

Modulation of immune function by dietary fatty acids.

Abstract: All mammals can synthesize fatty acids de novo from acetylCoA. The endproduct of the fatty acid synthetase (EC 2.3.1.85)enzymeispalmiticacid(l6: 0), whichinturncanbe elongated to stearic acid (1 8 : 0). There is little need for the synthesis of saturated fatty acids in Western man, since the diet normally supplies adequate amounts. However, cell membranes require unsaturated fatty acids to maintain their structure, fluidity and function; therefore, a mechanism for the introduction of double bonds (i.e. desaturation) exists. The introduction of a single double bond between C-9 and C10 is catalysed by the enzyme A'-desaturase, which is universally present in both plants and animals. This enzyme results in the conversion of stearic acid to oleic acid (18: ln-9). Plants, unlike animals, can insert additional double bonds into oleic acid between the existing double bond at the C-9 position and the methyl terminus of the C chain; a A12-desaturase converts oleic acid into linoleic acid (18 : 2n-6) while a A15-desaturase converts linoleic acid into a-linolenic acid (18 : 3n-3). Since animal tissues are unable to synthesize linoleic and alinolenic acids, these fatty acids must be consumed in the diet and so are termed essential fatty acids. Using the pathway outlined in Fig. 1, animal cells can convert dietary a-linolenic acid into eicosapentaenoic acid (20 : 51-3) and docosahexaenoic acid (22 : 6n-3); by a similar series of reactions dietary linoleic acid is converted via y-linolenic (18 : 3n-6) and dihomo-y-linolenic (20 : 3n-6) acids to arachidonic acid (20 : 4n-6). The n-9, n-6 and n-3 families of polyunsaturated fatty acids (PUFA) are not metabolically interconvertible in mammals. Many marine plants, especially the unicellular algae in phytoplankton, also carry out chain elongation and further desaturation of a-linolenic acid to yield the long-chain n-3 PUFA eicosapentaenoic and docosahexaenoic. It is the formation of these long-chain n-3 PUFA by marine algae and their transfer through the food chain to fish that accounts for their abundance in some marine fish oils.

Immunoregulatory and anti-inflammatory effects of n-3 polyunsaturated fatty acids

Abstract: 1. Fish oils are rich in the long-chain n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acids. Linseed oil and green plant tissues are rich in the precursor fatty acid, alpha-linolenic acid (18:3n-3). Most vegetable oils are rich in the n-6 PUFA linoleic acid (18:2n-6), the precursor of arachidonic acid (20:4n-6). 2. Arachidonic acid-derived eicosanoids such as prostaglandin E2 are pro-inflammatory and regulate the functions of cells of the immune system. Consumption of fish oils leads to replacement of arachidonic acid in cell membranes by eicosapentaenoic acid. This changes the amount and alters the balance of eicosanoids produced. 3. Consumption of fish oils diminishes lymphocyte proliferation, T-cell-mediated cytotoxicity, natural killer cell activity, macrophage-mediated cytotoxicity, monocyte and neutrophil chemotaxis, major histocompatibility class II expression and antigen presentation, production of pro-inflammatory cytokines (interleukins 1 and 6, tumour necrosis factor) and adhesion molecule expression. 4. Feeding laboratory animals fish oil reduces acute and chronic inflammatory responses, improves survival to endotoxin and in models of autoimmunity and prolongs the survival of grafted organs. 5. Feeding fish oil reduces cell-mediated immune responses. 6. Fish oil supplementation may be clinically useful in acute and chronic inflammatory conditions and following transplantation. 7. n-3 PUFAs may exert their effects by modulating signal transduction and/or gene expression within inflammatory and immune cells.

Eicosapentaenoic and docosahexaenoic acids alter rat spleen leukocyte fatty acid composition and prostaglandin E2 production but have different effects on lymphocyte functions and cell-mediated immunity

Abstract: Weanling rats were fed on high-fat (178 g/kg) diets which contained 4.4 g α-linolenic (ALA), γ-linolenic, arachidonic (ARA), eicosapentaenoic (EPA), or docosahexaenoic acid (DHA)/100 g total fatty acids. The proportions of all other fatty acids, apart from linoleic acid, and the proportion of total polyunsaturated fatty acids (PUFA) (approximately 35 g/100 g total fatty acids) were constant, and the n−6 to n−3 PUFA ratio was maintained as close to 7 as possible. The fatty acid compositions of the serum and of spleen leukocytes were markedly influenced by that of the diet. Prostaglandin E2 production was enhanced from leukocytes from rats fed the ARA-rich diet and was decreased from leukocytes from the EPA- or DHA-fed rats. Replacing dietary ALA with EPA resulted in diminished ex vivo lymphocyte proliferation and natural killer (NK) cell activity and a reduced cell-mediated immune response in vivo. In contrast, replacing ALA with DHA reduced ex vivo lymphocyte proliferation but did not affect ex vivo NK cell activity or the cell-mediated immune response in vivo. Replacement of a proportion of linoleic acid with either γ-linolenic acid or ARA did not affect lymphocyte proliferation, NK cell activity, or the cell-mediated immune response. Thus, this study shows that different n−3 PUFA exert different immunomodulatory actions, that EPA exerts more widespread and/or stronger immunomodulatory effects than DHA, that a low level of EPA is sufficient to influence the immune response, and that the immunomodulatory effects of fish oil may be mainly due to EPA.

Dietary fatty acids and lymphocyte functions.

Abstract: Lymphocytes are the cells that specifically recognize and respond to foreign antigens. They are present as circulating cells in blood and lymph, as anatomically-defined collections of cells in lymphoid organs (thymus, spleen, lymph nodes) or as scattered cells in other tissues. Lymphocytes exist as distinct subsets that have quite different functions and protein products, although they appear to be morphologically similar. The principal types of lymphocytes are T and B lymphocytes and natural killer (NK) cells; along with monocytes, lymphocytes are termed mononuclear cells.

n-3 Polyunsaturated fatty acids and mononuclear phagocyte function

Abstract: The macrophage is the major differentiated cell of the mononuclear phagocyte system. This system comprises bone marrow monoblasts and promonocytes, peripheral blood monocytes and tissue macrophages. Macrophages are widely distributed in the body, displaying great structural and functional heterogeneity. The precursors of these cells originate in the bone marrow, from which incompletely differentiated monocytes enter the peripheral blood. Monocytes are 10 to 20 µm in diameter and have well developed Golgi apparatus, numerous lysosomal granules, evenly distributed mitochondria and a single kidney-shaped nucleus; their half life in the bloodstream is relatively short (< 70 h). Once they have settled in a tissue (such as connective tissue, liver, lung or the peritoneal cavity), monocytes mature and become macrophages. Macrophages are larger than monocytes (10 to 80 µm in diameter) and have an oval-shaped nucleus, a cytoplasm containing numerous dense granules, endocytic vesicles, mitochondria and lysosomes and many pseudopodia extending from the cell surface. In contrast to the short half life of monocytes, macrophages remain in tissues for many months, perhaps even years. Often they are named to designate specific locations; for example, in the central nervous system they are called microglia and in the vascular sinusoids of the liver they are called Kupffer cells. Macrophages sometimes stay relatively quiescent as resident cells; these are tissue macrophages that have not encountered foreign materials and have low functional activities.

Dietary fatty acids and the immune system

Abstract: An effect of dietary fatty acids upon the immune system was suggested by early epidemiological studies of the incidence of multiple sclerosis and by the observations that the blood, cells, and tissues of patients with multiple sclerosis are deficient in long-chain polyunsaturated fatty acids (PUFA) (1). This suggestion was supported by observations that linoleic (18:2n-6) and arachidonic (20:4n-6) acids inhibit mitogenstimulated proliferation of human peripheral blood lymphocytes in culture (see Ref. 2) and that subcutaneous injections of these fatty acids prolong the survival of skin allografts in mice (3). These studies focused on the n-6 family of PUFA, but more recently there has been intense interest in the effects of the n-3 PUFA. An immunomodulatory effect of these latter fatty acids is suggested by epidemiological studies which show that populations such as Greenland Eskimos, who consume large quantities of marine mammal and fish oils which are rich in eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acids, have a very low incidence of inflammatory and autoimmune disorders (4). Furthermore, a number of clinical studies reported that fish oil supplementation has some beneficial effects in rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease and prolongs the survival of grafts (see Refs. 5,6). The potential clinical use of oils rich in n-6 or n-3 PUFA has given rise to a number of investigations of the effects of fatty acids and dietary oils upon immune cell functions (see Ref. 7). Dietary fa t~ acids and immunity: An overview. A number of studies showed that feeding rats, mice, rabbits, or chickens diets rich in fish oil results in suppressed ex vivo lymphocyte proliferation (8-13), interleukin-2 (IL-2) production (14), natural killer (NK) cell activity (12,15-17), cytokine [(IL1, IL-6, tumor necrosis factor (TNF)] production by inflammatory macrophages (18-20), and macrophage-mediated cytotoxicity (20-22). Recent studies indicate that relatively low levels of n3 PUFA are required to bring about some of these suppressive effects (23,24), that dietary eicosapentaenoic and docosahexaenoic acids both inhibit lymphocyte proliferation (14,23), and that dietary eicosapentaenoic acid but not docosahexaenoic acid inhibits NK cell activity (23). Feeding laboratory animals