I

Atherosclerosis

Stroke

Myocardial infarction

Figure 5 Linkage between inflammation as part of the defense against infection and as a factor in insulin insensitivity and disease processes.

Influence of Nutrients on Cytokine Biology

Proinflammatory cytokines exert widespread effects on metabolism, involving alterations in lipid, carbohydrate, and protein metabolism. In addition, there are substantial changes in micronutrient metabolism. A number of intracellular signaling pathways are activated by the actions of cytokines on target cells, including prostaglandins and leukotrienes, cyclic AMP, and protein kinase C. There are thus many levels at which nutrient intake can modify the intensity and characteristics of the response to inflammatory stimuli. The ability of nutrients to modify inflammation has been used in the treatment of diseases with an inflammatory basis. The interaction between nutritional status and inflammation is also important in public health because it determines the effects of infection on growth and well-being of populations with a poor nutrient intake.

The earliest indications that nutritional status could affect cytokine biology came from studies on malnourished hospital patients. White blood cells from patients had a reduced capacity to produce cytokines. The high mortality rates in these patients highlighted the importance of cytokines in the process of recovery from injury and infection. Protein supplements improved cytokine production and decreased the mortality rate. Since these observations were made, a large number of studies have been conducted in animals and human volunteers that show that fats, amino acids, and micronutrients change the ability of mammals to produce and respond to IL-1, IL-6, and TNF (Figure 6). Figure 6

Infection Trauma Chronic inflammatory

Infection Trauma Chronic inflammatory

disease

Target tissue responsiveness disease

Target tissue responsiveness n-6 PUFAs Vitamin E deficiency

Protein deficiency n-3 PUFAs f+ n-6 PUFAs n-3 PUFAs n-9 MUFAs Protein deficiency Sulfur amino acid deficiency

Biological/pathological effect

Figure 6 Summary of the effects of nutrients and nutritional conditions on cytokine biology. A stimulatory effect is indicated by a plus sign and an inhibitory influence by a minus sign.

indicates whether a change in the intake of a nutrient, or nutrient status, alters cytokine production or the response of target tissues to the actions of cytokines.

Influence of Fats on Cytokine Production and Effects

Dietary fats can be divided into four main types. Some are rich in n-6 polyunsaturated fatty acids (PUFAs); fats in this group include corn, sunflower, and safflower oils. Some are rich in n-3 PUFAs; these include fats from marine sources. Some are rich in monounsaturated fatty acids; these include olive oil and butter. Some fats are characterized by a high content of saturated fatty acids, usually accompanied by low concentrations of PUFAs; coconut oil, butter, suet, and lard are in this category.

The production and actions of pro-inflammatory cytokines are profoundly influenced by dietary fat intake. There are a number of levels at which fats may modify cytokine biology. Most relate to the ability of fats to change the fatty acid composition of membrane phospholipids. Subsequently, membrane fluidity may be changed, the types and amounts of prostaglandins and leukotrienes produced during inflammation may be altered, and the synthesis of a number of cellular mediators that arise from phospholipids (platelet activating factor, dia-cylglycerol, and ceramide) may also be changed. As a result of these changes, the binding of cytokines to target tissues and the intensity of the inflammatory response may be altered.

Phospholipids contain two fatty acid chains attached to the remainder of the molecule at positions designated sn1 and sn2. Normally, arachidonic acid (AA C20:4 n-60) is released from this position and provides the parent compound for prostaglan-dins and leukotrienes. However, the long-chain PUFA eicosapentaenoic acid (EPA C20:5 n-3) may compete with AA for insertion at sn2. Prostaglan-dins and leukotrienes with a much lower bioactivity may result. This biological effect may account in part for the anti-inflammatory effects of fish oil. Many animal studies indicate that fats rich in n-6 PUFAs exert a pro-inflammatory influence, whereas fats rich in monounsaturated fatty acids or n-3 PUFA have the opposite influence. In human studies, however, evidence for the influence of n-6 PUFA or monounsaturated fatty acids is not so clear-cut. It has been postulated that the major increase in inflammatory disease that has occurred in the past 40 years in industrialized countries is due to a major

increase in the intake of n-6 PUFAs during this time (from approximately 5 to 7% of dietary energy). It has also been postulated that the lower levels of inflammatory disease associated with the habitual consumption of a 'Mediterranean diet' are due in part to high intakes of monounsaturated fatty acids. The evidence for n-3 PUFAs producing an anti-inflammatory effect in humans is much stronger, however. Also, n-3 PUFAs have been shown to produce beneficial effects in inflammatory disease. In many double-blind, randomised controlled clinical trials, fish oil produced significant clinical benefit in patients with rheumatoid arthritis. A number of trials also report beneficial effects of fish oil in the treatment of Crohn's disease. The precise mechanisms for these effects is unclear. A number of studies have demonstrated the ability of fish oil to reduce pro-inflammatory cytokine production and to alter the production of eicosanoids. However, recent studies have indicated a genomic influence on the ability of fish oil to reduce TNF production, thus indicating that fish oil may not be universally effective as an anti-inflammatory agent. A fish oil and vitamin E intervention trial (GISSI) was carried out on 11,324 survivors of a myocardial infarct in Italy. Patients were given 1 g of n-3 PUFA and/or 300 mg vitamin E/d. In the GISSI trial, fish oil supplements were shown to reduce the chance of stroke or a second myocardial infarct by 15%. Because inflammation plays a role in atherosclerosis, it is interesting to note that a trial of fish oil in patients with severe atherosclerosis showed that a supplement of 6 g/day of fish oil for 7 weeks significantly reduced macrophage activity in plaques.

Modulation of Cytokine Biology by Amino Acid and Protein Intake

Substantial increases occur in protein synthesis as the result of infection. It has been estimated that approximately 45 g of protein is required to produce and maintain the increased quantities of white blood cells and acute phase proteins in an infected individual. This demand will have a considerable impact on the availability of amino acids for other processes in the body that involve protein synthesis. The inhibitory effect of infection on growth, pregnancy, and lactation is well recognized. Output of amino acids from skeletal muscle, skin, and bone provides substrate for the synthesis of cells and proteins associated with the response to infection and trauma, as indicated previously. However, the supply may not always match demand, as is evident from the decrease in plasma concentrations of a number of amino acids. In particular, reductions occur in the concentrations of a metabolically related group of amino acids, including glycine, serine, and taurine. All three are metabolically related with the sulfur amino acids. Glycine and serine, together with the sulfur amino acids, are found in high concentrations in many compounds associated with the immune and inflammatory response, most notably comprising 66% of glu-tathione, 56% of metallothionein, and up to 25% of many acute-phase proteins. Experimental studies have shown that the production of cytokines, acute-phase proteins, and glutathione is influenced by the adequacy of both protein and sulfur amino acid intake. The partitioning of cysteine into glutathione and proteins in the liver may change if dietary sulfur amino acid intake becomes inadequate. This phenomenon is due to the biochemical properties of rate-limiting enzymes in both pathways. Whereas the Km for 7-glutamyl cysteine synthetase (rate limiting for GSH synthesis) is 0.35 mM, that for amino acid activating enzymes (rate limiting for protein synthesis) is only 0.003 mM. This biochemical characteristic means that the GSH synthesis will fall below maximal rates at much higher intracellular cysteine concentrations than protein synthesis. Thus, at low sulfur amino acid intakes antioxidant defenses will become compromised. Low concentrations of GSH in tissues may have implications for the extent of inflammatory processes in the individual. In animal studies, decreased lung GSH concentrations are associated with the accumulation of inflammatory cells in tissues. In studies on HIV patients given N-acetyl cysteine, to improve GSH status, a decrease in plasma IL-6 concentrations has been noted indicating a reduction in inflammation. In view of the effects of NF-kB activation on HIV replication, it is interesting to note that the drug also brought about a reduction in HIV mRNA levels.

Modulation of Cytokine Biology by Micronutrients

Micronutrients play varied and complex roles in the response to infection and trauma. They are incorporated into substances that are synthesized in increased amounts during the response and into components of antioxidant defence, and they also modulate immune function. Trace elements are present in several acute-phase proteins and enzymes associated with antioxidant defense (Figure 4). These proteins include metallothionein (Zn), caerulo-plasmin (Cu), superoxide dismutases (Mn, Cu, and Zn), and glutathione peroxidase (Se). Deficiencies in copper impair the ability of rats to increase superoxide dismutase and caeruloplasmin activities in response to inflammatory agents. Deficiencies in zinc impair the ability to increase metallothionein synthesis; furthermore, zinc deficiency has potent suppressive effects on lymphocyte proliferation. Iron status may influence inflammation and immune function in a number of ways. Normally, iron is tightly bound to transport proteins such as transferrin and ferritin. However, following tissue damage and infections such as malaria, which may destroy red blood cells, free iron may be released and exert a proinflammatory effect by catalyzing free radical production. The latter effect may activate NF-kB and upregulate cytokine production. Indeed, iron dextran infusion has been shown to exacerbate inflammatory symptoms in rheumatoid arthritis. Desferrioximine, an iron chelator, suppresses TNF and IL-1 production by rodent macrophages. Iron deficiency also decreases the ability of such cells to produce cytokines. Impairment of immunological defence is commonly found in iron-deficient animals and human populations. Defects occur in T cell proliferation and in the ability of macrophages to engulf and kill bacteria. The latter may relate to the role of iron as part of the NADPH oxidase complex that is responsible for the respiratory burst and generation of hydroxyl radicals that kill bacteria. Myeloperoxidase activity generates hypochlorous acid for bacterial killing, and myeloperoxidase is also a hemoprotein whose activity is decreased by iron deficiency.

Vitamins also exert a number of effects on cyto-kine biology. These effects may relate to the roles that some of these nutrients play as antioxidants and growth factors (Figure 4). Rats deficient in vitamin E exhibit an enhanced inflammatory response to endotoxin; addition of the vitamin to the diet will suppress this effect. In healthy subjects and smokers, a daily dose of 600IU of vitamin E for 4 weeks reduces the ability of white blood cells to produce TNF and IL-1. Cigarette smoking enhances cytokine production and raises acute-phase protein concentrations. The extent of the elevation is inversely related to vitamin E. Strenuous exercise results in a small increase in plasma concentrations of IL-1 and IL-6; vitamin E supplementation will prevent this effect.

Vitamin A status also influences cytokine production, although the mechanism underlying the effect is unclear. Macrophages taken from Indian children who received a supplement of 100 000 IU of retinol produced seven times the quantity of IL-1 produced by cells of children who had not received supplementation. The effect may be more pharmacological than nutritional in nature. Mice given vitamin A at a dose that was 16 times their requirement had macrophages that produced twice as much IL-1 upon stimulation than cells from unsupplemented animals.

Hormone-like properties have been attributed to vitamin D in relation to its effects on calcium. It is apparent that endocrine effects of the vitamin extend to immune function. Macrophages treated with 1,25-dihydroxyvitamin D3 produce increased amounts of TNF and were more effective at killing Mycobacterium avium than untreated cells.

Vitamin B6 supplementation has been found to increase lymphocyte proliferation and production of IL-2 in elderly subjects. The effect of the vitamin on pro-inflammatory cytokine production is unknown. Little is known about the effects of other water-soluble vitamins on cytokine biology. Although no effects of vitamin C status on pro-inflammatory cytokine production have been reported, doses of the vitamin reduce the incidence of respiratory infections in longdistance marathon runners.

Conclusions

The objective of the response of the body to infection and trauma is to disadvantage and destroy invading organisms while simultaneously protecting healthy tissues from the damaging influence of compounds produced during the response. Cytokines play a central role in the protection of the animal from damage during the response. The close interrelationship between pro-inflammatory cytokines, oxidant molecules, and antioxidant defenses gives a biological advantage to the host (Figure 7).

Nutrients

Antioxidant defenses

Objective

Nutrients

Antioxidant defenses

Antigen destruction tissue protection

Cytokine production

Infection/Trauma

Nutrients

Stimulus

Figure 7 Influence of nutrients on the coordinated inflammatory events for destroying pathogens and protecting the host. Direct and indirect effects of nutrients are shown as solid and broken lines, respectively.

The essence of survival of an individual or species lies in the ability to prioritize physiological processes, particularly those processes that exert a large metabolic demand. Thus, at various times throughout the life cycle mammals will focus metabolic processes on achieving growth, the construction of placenta and fetus, the synthesis of milk components, or the repulsion of invasion by pathogens. For the infected individual, the marshalling of resources to combat the invading pathogen must assume a priority over all other physiological events. These other physiological processes can continue once the invasion has been repulsed and the damage done by the invader has been repaired.

The production of cytokines and other molecules associated with the inflammatory process carries risks of damage to the host as well as a survival advantage. The risk to the host is minimized by a sophisticated range of feedback control systems and synthesis of substances that protect the host. As discussed previously, nutrient intake modulates cytokine biology and the control and protective systems. A wide range of nutrients modulate cytokine biology at the level of production and sensitivity of target tissues (Figure 6). As a consequence of the modulation, the extent of depletion of nutrient stores and the risk of damage during the inflammatory response will be changed. The extent of tissue depletion and risk to the host will thus range from mild and transient in nature to severe, chronic, or lethal in effect.

See also: Amino Acids: Chemistry and Classification; Metabolism. Diabetes Mellitus: Classification and Chemical Pathology. Fatty Acids: Monounsaturated; Omega-3 Polyunsaturated; Omega-6 Polyunsaturated; Saturated. Fish. Obesity: Definition, Etiology and Assessment. Vitamin A: Biochemistry and Physiological Role. Vitamin E: Metabolism and Requirements. Zinc: Physiology.

Further Reading

Beutler B and Cerami A (1986) Tumor necrosis factor as two sides of the same biological coin. Nature 320: 584-588.

Dinarello CA (1988) Biology of IL1. FASEB Journal 1: 108-115.

Douglas RG and Shaw JHF (1989) Metabolic response to sepsis and trauma. Bristish Journal of Trauma 76: 115-122.

GISSI-Prevenzione Investigators (1999) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet 354: 447-455.

Grimble RF (1994) Nutritional antioxidants and the modulation of inflammation: The theory and the practice. Critical Care Medicine 2: 175-185.

Grimble RF (1996) The interaction between nutrients, proinflammatory cytokines and inflammation. Clinical Science 91: 121-130.

Grimble RF (2002) Inflammatory status and insulin resistance. Current Opinion in Clinical Nutrition and Metabolic Care 5: 551-559.

Grimble RF (2003) Inflammatory response in the elderly. Current Opinion in Clinical Nutrition and Metabolic Care 6: 21-29.

Grimble RF, Howell WM, O'Reilly G et al. (2002) The ability of fish oil to suppress tumor necrosis factor-alpha production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes which influence TNF-alpha production. American Journal of Clinical Nutrition 76: 454-459.

Grunfeld C and Feingold KR (1992) Tumour necrosis factor, interleukin 1 and interferon induce changes in lipid metabolism as part of host defence. Proceedings of the Society of Experimental Biology and Medicine 200: 214-227.

Heinrich PC, Castell JV, and Andus T (1990) Interleukin 6 and the acute phase response. Biochemical Journal 265: 621-636.

Murray MJ and Murray AB (1980) Cachexia: A 'last ditch' mechanism of host defence. Journal of the Royal College of Physicians (London) 14: 197-199.

Newsholme P and Newsholme EA (1989) Rates of utilisation of glucose, glutamine and oleate and end product production by mouse macrophages in culture. Biochemical Journal 261: 211-218.

Paolini-Giacobino A, Grimble R, and Pichard C (2003) Genomic interactions with disease and nutrition. Clinical Nutrition 22: 507-514.

Schreck R, Rieber P, and Baeurerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers of NFreB transcription factor and HIV1. EMBO Journal 10: 2247-2256.

Thies F, Garry JMC, Yaqoob P et al. (2003) Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: A randomized trial. Lancet 361: 477-485.

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