Changes in eicosanoid synthesis

A key link between fatty acids, inflammation and immune function is a group of bioactive mediators termed eicosanoids (prostaglandins, leucotrienes, thromboxanes), which are synthesized from 20-carbon PUFAs (Fig. 4.4). The two y-Linolenic acid (18:3n-6)

DGLA -^ Arachidonic acid epa

5-LOX

15-LOX

5-LOX

5-LOX

5-LOX

15-LOX

5-LOX

5-LOX

PGE1

LTB3

15-OH-DGLA PGE2

ltb4

PGE3

LTB;

TXA1

LTC3

txa2

ltc4

TXA3

LTC

ltd4

LTD

lte4

LTE.

5-HETE

Fig. 4.4. Outline of synthesis of eicosanoids from 20-carbon n-6 and n-3 polyunsaturated fatty acids. COX, cyclo-oxygenase; DGLA, dihomo-7-linolenic acid; EPA, eicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; LOX, lipoxygenase; LT, leucotriene; PG, prostaglandin; TX, thromboxane.

major pathways for eicosanoid synthesis are via the enzymes cyclo-oxygenase (COX) and lipoxygenase (LOX). These enzymes initiate pathways that result in the production of prostaglandins/thromboxanes and leucotrienes/hydroxy-eicosatrienoic acids/lipoxins, respectively. Membrane arachidonic acid is the main precursor of these mediators, giving rise to dienoic prostaglandins (e.g. PGE2) and thromboxanes (TXA2) and tetraenoic leucotrienes (e.g. LTB4). Arachidonic acid in cell membranes is mobilized by various phospholipase enzymes, most notably phospholipase A2, and the released arachidonic acid is the substrate for COX or one of the three LOX enzymes (Fig. 4.5). There are at least 16 different 2-series PG and these are formed in a cell-specific manner. For example, monocytes and macrophages produce large amounts of PGE2 and PGF2, neutrophils produce moderate amounts of PGE2 and mast cells produce PGDg. The LOX enzymes have different tissue distributions, with 5-LOX being found mainly in mast cells, monocytes, macrophages and granulocytes and 12- and 15-LOX being found primarily in epithelial cells. Metabolism of arachidonic acid by the 5-LOX pathway gives rise to hydroxy and hydroperoxy derivatives (5-hydroxyeicosatetraenoic acid) (5-HETE) and 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), respectively) and the 4-series LT (Fig. 4.5).

Eicosanoids (particularly PGE2 and 4-series LT) are involved in modulating the intensity and duration of inflammatory and immune responses (for reviews, see Kinsella et al., 1990; Lewis et al., 1990; Tilley et al., 2001). The pro-inflammatory effects of PGE2 include inducing fever, increasing vascular permeability pgj2 pge2 pgi2 pgf2 txa2

5-LOX

5-LOX

Ltb4 Inflammation

5-HETE

pgj2 pge2 pgi2 pgf2 txa2

LTC4 LTB4 Lipoxin A4

Lipoxin B4

5-HETE

LTC4 LTB4 Lipoxin A4

LTD4

LTE,

Lipoxin B4

Fig. 4.5. Synthesis of eicosanoids from arachidonic acid. COX, cyclo-oxygenase; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LOX, lipoxygenase; LT, leucotriene; PG, prostaglandin; TX, thromboxane.

and vasodilatation and enhancing pain and oedema caused by other agents, such as histamine. Additionally, PGE2 suppresses lymphocyte proliferation and natural killer cell activity and inhibits production of TNF-a, IL-1, IL-6, IL-2 and IFN-7 (Fig. 4.6); thus, in these respects, PGE2 is immunosuppressive and antiinflammatory. PGE2 does not affect the production of the T-helper 2 (Th2)-type cytokines IL-4 and IL-10, but promotes immunoglobulin E (IgE) production by B lymphocytes (Fig. 4.6). LTB4 increases vascular permeability, enhances local blood flow, is a potent chemotactic agent for leucocytes, induces release of lysosomal enzymes, enhances generation of reactive oxygen species, inhibits lymphocyte proliferation and promotes natural killer cell activity (Fig. 4.7). In addition, 4-series LT regulate the production of pro-inflammatory cytokines; for example, LTB4 enhances production of TNF-a, IL-1, IL-6, IL-2 and IFN-7 (Fig. 4.7). Whereas 15-HETE inhibits lymphocyte proliferation, 5-HETE enhances it. Thus, arachidonic acid gives rise to a range of mediators that have opposing effects to one another, so the overall physiological effect will be the result of the balance of these mediators, the timing of their production and the sensitivities of target cells to their effects.

Dietary fatty acids can influence eicosanoid synthesis by affecting the supply of substrates. Feeding animals or humans increased amounts of fish oil results in a decrease in the amount of arachidonic acid in the membranes of most cells in the body, including those involved in inflammation and immunity,

Proliferation

Fig. 4.6. Immunoregulatory roles of PGE2. IFN-7, interferon-7; IgE, immunoglobulin E; IL, interleukin; PG, prostaglandin; TNF, tumour necrosis factor.

Arachidonic acid

Arachidonic acid

Pge2 Interferon

Proliferation

Fig. 4.6. Immunoregulatory roles of PGE2. IFN-7, interferon-7; IgE, immunoglobulin E; IL, interleukin; PG, prostaglandin; TNF, tumour necrosis factor.

Arachidonic acid

Arachidonic acid

Anti Tumour Neutrophil
Fig. 4.7. Immunoregulatory roles of LTB4. IFN-7, interferon-7; IL, interleukin; LT, leucotriene; TNF, tumour necrosis factor.

such as monocytes, macrophages, neutrophils and lymphocytes (see earlier section). This means that there is less arachidonic acid available for the synthesis of eicosanoids. Consequently, dietary fish oil decreases the production of arachidonic acid-derived eicosanoids from animal (Lokesh et al., 1986; Brouard and Pascaud, 1990; Yaqoob and Calder, 1995; Peterson et al., 1998; Fig. 4.8) and human (Lee et al., 1985; Endres et al., 1989; Meydani et al., 1991; Sperling et al., 1993; Caughey et al., 1996) immune cells. EPA is also a substrate for the COX and LOX enzymes, resulting in the synthesis of the trienoic prostanoids (e.g. PGE3) and pentaenoic leucotrienes (e.g. LTB5) (Fig. 4.4). The eicosanoids produced from EPA are often less biologically potent than the analogues synthesized from arachidonic acid. For example, LTB5 is only about 10% as potent as LTB4 as a chemotactic agent and in promoting lysosomal enzyme release (see Kinsella et al., 1990). Since dietary fish oil leads to decreased PGE2 production, it is often stated that feeding n-3 lipids should result in a reversal of the effects of PGE2. Thus, fish oil is expected to

Low fat Coconut oil Olive oil Safflower oil Fish oil Diet

Fig. 4.8. Effect of dietary fish oil on the production of prostaglandin E2 (PGE2) by macrophages. Mice were fed for 8 weeks on a low-fat (25 g kg-1 maize oil) diet or on diets containing 200 g kg-1 of either hyrogenated coconut oil, olive oil, safflower oil or fish oil. Thioglycollate-elicited peritoneal macrophages were prepared and cultured with bacterial lipopolysaccharide (10 ^g ml-1) for 8 h. The medium was collected and PGE2 concentrations were measured by ELISA. (Data are from Yaqoob and Calder, 1995.)

result in less inflammation, enhanced cytokine production by monocytes/ macrophages and Th1 lymphocytes and enhanced lymphocyte proliferation (Fig. 4.9). The reduction in the generation of arachidonic acid-derived mediators that accompanies fish oil consumption has led to the idea that fish oil is anti-inflammatory and might enhance immune function (Fig. 4.9). However, the in vivo situation is likely to be more complex than this, because PGE2 is not the sole mediator produced from arachidonic acid and the range of mediators produced have varying, sometimes opposite, actions (see above). Furthermore, EPA will give rise to mediators with varying actions, some of which may actually be the same as those of the analogues produced from arachidonic acid. Thus, the overall effect of fish oil feeding cannot be predicted solely on the basis of an abrogation of PGE2-mediated effects. Furthermore, a number of the effects of n-3 PUFA have been shown to occur independent of changes in eicosanoid production (Santoli et al., 1990; Calder et al., 1992; Soyland et al., 1993).

Coconut Oil - The Healthy Fat

Coconut Oil - The Healthy Fat

The coconut tree is one of the most versatile plants in existence. Whilst we are all familiar with the coconut as a food source not many of us know the myriad of other benefits the coconut holds.

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