Alterations in membrane structure and composition

Immune-cell activation results in both de novo synthesis and an increased turnover of membrane phospholipids (e.g. Resch et al., 1972; Ferber et al., 1975). Therefore, essential fatty acids would be required for the synthesis of new membranes during immune-cell responses, especially those involving increased membrane synthesis and turnover (e.g. cell proliferation, phagocytosis).

The fluidity of the plasma membrane or of regions of the plasma membrane is important in the functioning of cells (see Stubbs and Smith, 1984). The fluidity of a membrane is determined by its lipid components and their fatty-acid composition (Stubbs and Smith, 1984). Membrane fluidity is an important regulator of phagocytosis (Calder et al., 1990). The function of the immune system depends on interactions between different cell types and, through effects on membrane composition, dietary fatty acids have the potential to influence these interactions. For example, the interaction of cytotoxic T-cells with target cell membranes, a necessary interaction to induce effector function, is affected by the fluidity of the plasma membrane of the T-cells (Bialick et al., 1984). Cell culture experiments have demonstrated that changes in fatty-acid composition of immune cells alter membrane fluidity (e.g. Calder et al., 1994), but this has been less easy to demonstrate after dietary manipulations (e.g. Yaqoob et al., 1995), probably because the fatty acid composition changes induced by diet are less extreme than those seen in culture and because, in the intact animal, mechanisms to counter the fluidizing effect of increasing the PUFA content of membranes (e.g. insertion of cholesterol) can be achieved more readily than in culture.

Since there has been significant focus on the effects of n-6 and n-3 PUFAs in inflammation and immunity, the proportions of those classes of fatty acids in immune cells are of interest. The exact proportion of arachidonic acid in human immune cells varies according to cell type and the lipid fraction examined (Gibney and Hunter, 1993; Sperling et al., 1993). The phospholipids of human mononuclear cells (an approximately 70: 20: 10 mixture of T lymphocytes, B lymphocytes and monocytes purified from human blood) contain 6-10% linoleic acid, 1-2% dihomo-7-linolenic acid (DGLA) and 15-25% arachidonic acid (Gibney and Hunter, 1993; Yaqoob et al., 2000; see Table 4.2). In contrast, the proportions of n-3 fatty acids are low: a-linolenic acid is generally found only in trace amounts and EPA and DHA comprise only 0.1-0.8% and 2-4%, respectively (Gibney and Hunter, 1993; Yaqoob et al., 2000; see Table 4.2).

Animal studies show that decreasing the availability of linoleic acid in the diet, especially by replacing it with n-3 fatty acids (either a-linolenic acid or long-chain n-3 fatty acids), results in decreased proportions of all n-6 fatty acids, including arachidonic acid, in immune-cell phospholipids (Marshall and Johnston, 1985; Lokesh et al., 1986; Brouard and Pascaud, 1990; Yaqoob et al., 1995; Jeffery et al., 1996; Peterson et al., 1998; Robinson and Field, 1998; Wallace et al., 2000, 2001; Robinson et al., 2001). When a-linolenic acid is added to the human diet in significant quantities, it appears in immune cells and there is also an increase in the proportion of EPA, although the proportion of DHA may not be elevated (Caughey et al., 1996). More moderate increases in the amount of a-linolenic acid in the human diet appear to have a limited impact on immune-cell fatty-acid composition (Healy et al., 2000; Thies et al., 2001c). When fish oil is provided in the human diet, the proportions of EPA and DHA in immune cells are significantly elevated and the n-6/n-3 PUFA ratio is decreased (Lee et al., 1985; Endres et al., 1989; Fisher et al., 1990; Molvig et al., 1991; Gibney and Hunter, 1993; Sperling et al., 1993; Caughey et al.,

Table 4.2. Fatty-acid composition of human mononuclear cells before and after supplementation of the diet with evening primrose oil or fish oil. Healthy volunteers supplemented their diet with 9 g evening primrose oil (providing 1 g 7-linolenic acid) day-1 or with 9 g fish oil (providing 3.2 g EPA plus DHA) day-1 for 8 weeks. Mononuclear cells were isolated by standard techniques and the fatty-acid composition determined. (Data are mean ± standard error of mean (SEM) for six subjects per group and are taken from Yaqoob et al., 2000.)

Fatty acid (g 100 g 1 of total fatty acids)

Evening primrose oil

Fish oil

Fatty acid

Before

After

Before

After

Dihomo-7-linolenic acid Arachidonic acid EPA DHA

  1. 2 ±0.4 2.2 ±0.4a
  2. 6 ±2.1 21.2 ±0.5
  3. 0 ±0.3 1.1 ±0.4
  4. 7 ±0.4 2.6 ±0.4
  5. 3 ±0.5 1.9 ±0.5
  6. 3 ±0.8 18.8 ±1.3a
  7. 8 ±0.4 2.8 ±0.2a
  8. 9 ±0.5 3.3 ±0.3

indicates significantly different from before supplementation.

1996; Healy et al., 2000; Yaqoob et al., 2000; Thies et al., 2001c; see Table 4.2) in a dose-dependent manner. Similar effects occur in neutrophils, monocytes and T and B lymphocytes (Gibney and Hunter, 1993). In many studies, the degree of enrichment of EPA is greater than that of DHA (e.g. 300% vs. 95%: Yaqoob et al., 2000), although this probably depends upon the relative amounts of EPA and DHA in the fish oil preparation. The incorporation of the long-chain n-3 fatty acids is at least partly at the expense of arachidonic acid (see Table 4.2) and is considered to be near maximal 4 weeks after a dietary change (e.g. Healy et al., 2000; Yaqoob et al., 2000; Thies et al., 2001c). Since n-3 PUFAs oxidize more readily than n-6 PUFAs, they may increase susceptibility of cellular membranes to lipid peroxidation. Increased free radical production has been demonstrated in animals fed diets rich in n-3 PUFAs. The risk of oxidation associated with increased intake of n-3 PUFA has been shown to be minimized by intake of extra antioxidants, such as vitamin E.

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