Altered monocyte CD44 expression in peripheral arterial disease is corrected by fish oil supplementation.

BACKGROUND AND AIMS: CD44 and its splice variants can be expressed on all leukocytes, conferring adhesive properties and enhancing cellular recruitment to the endothelium during inflammation. CD44 expression is increased in inflammatory conditions such as rheumatoid arthritis and CD44 variant 3 (CD44v3) expression may be associated with inflammation. We have examined CD44 and CD44v3 expression on peripheral blood monocytes from patients with peripheral arterial disease (PAD) and healthy controls. We have also examined the effect of fish oil supplementation on these markers. METHODS AND RESULTS: CD44 and CD44v3 were assessed at baseline and following dietary supplementation with fish oil for 12 weeks in both PAD and control groups. Monocytes from PAD patients had higher CD44 expression than those from controls (median intensity fluorescence (MIF): 480+/-278 vs 336+/-251 (mean+/-SD); p<0.001). Following 12 weeks' dietary supplementation with fish oil, CD44 expression was reduced in PAD patients (MIF: 480+/-278 vs 427+/-262; p=0.05) but not in controls (336+/-251 vs 355+/-280; ns). Monocyte CD44v3 expression was lower in cultured monocytes from PAD patients compared to those from controls (0.15+/-0.15 vs 0.22+/-0.14 OD units; p<0.02). This was increased in the PAD group following fish oil supplementation (0.15+/-0.14 to 0.27+/-0.23 OD units; p<0.001). CONCLUSION: Monocyte CD44 and CD44v3 expression are altered in arterial disease but are returned towards levels seen in control subjects by dietary fish oil supplementation.

Nutrition in clinical practice-the refeeding syndrome: illustrative cases and guidelines for prevention and treatment.

The refeeding syndrome is a potentially lethal complication of refeeding in patients who are severely malnourished from whatever cause. Too rapid refeeding, particularly with carbohydrate may precipitate a number of metabolic and pathophysiological complications, which may adversely affect the cardiac, respiratory, haematological, hepatic and neuromuscular systems leading to clinical complications and even death. We aimed to review the development of the refeeding syndrome in a variety of situations and, from this and the literature, devise guidelines to prevent and treat the condition. We report seven cases illustrating different aspects of the refeeding syndrome and the measures used to treat it. The specific complications encountered, their physiological mechanisms, identification of patients at risk, and prevention and treatment are discussed. Each case developed one or more of the features of the refeeding syndrome including deficiencies and low plasma levels of potassium, phosphate, magnesium and thiamine combined with salt and water retention. These responded to specific interventions. In most cases, these abnormalities could have been anticipated and prevented. The main features of the refeeding syndrome are described with a protocol to anticipate, prevent and treat the condition in adults.

Polyunsaturated fatty acids, inflammation and immunity.

Consumption of n-6 polyunsaturated fatty acids greatly exceeds that of n-3 polyunsaturated fatty acids. The n-6 polyunsaturated fatty acid arachidonic gives rise to the eicosanoid family of inflammatory mediators (prostaglandins, leukotrienes and related metabolites) and through these regulates the activities of inflammatory cells, the production of cytokines and the various balances within the immune system. Fish oil and oily fish are good sources of long chain n-3 polyunsaturated fatty acids. Consumption of these fatty acids decreases the amount of arachidonic acid in cell membranes and so available for eicosanoid production. Thus, n-3 polyunsaturated fatty acids act as arachidonic acid antagonists. Components of both natural and acquired immunity, including the production of key inflammatory cytokines, can be affected by n-3 polyunsaturated fatty acids. Although some of the effects of n-3 fatty acids may be brought about by modulation of the amount and types of eicosanoids made, it is possible that these fatty acids might elicit some of their effects by eicosanoid-independent mechanisms. Such n-3 fatty acid-induced effects may be of use as a therapy for acute and chronic inflammation, and for disorders which involve an inappropriately activated immune response.

Nutritional modulation of immune function.

The inflammatory response to injury and infection, although an essential part of immune function, carries the risk of severe tissue depletion and immunosuppression. These outcomes increase morbidity and delay recovery. Evidence is accumulating that single-nucleotide polymorphisms in the genes controlling pro-inflammatory cytokine production adversely influence the response. Immunonutrition provides a means of modulating the inflammatory response to injury and infection, and thereby improves clinical outcome. n-3 Polyunsaturated fatty acids (n-3 PUFA), glutamine, arginine, S amino acids and nucleotides are important components of immunonutrient mixes. While animal model studies suggest that all these components may exert a beneficial effect in patients, the number of large randomized placebo-controlled trials utilizing immunonutrition is fairly limited and the observed effects are relatively small. Meta-analyses suggest that while immunonutrition may not reduce mortality rates, a reduction in hospital length of stay, decreased requirements for ventilation and lower infection rates are achieved by this mode of nutrition. The present paper discusses some underlying reasons for the difficulty in demonstrating the clinical efficacy of immunonutrition. Paramount among these reasons is the antioxidant status and genetic background of the patient. A number of studies suggest that there is an inverse relationship between inflammation and T-cell function. Immuno-enhancive effects have been shown in a number of studies in which n-3 PUFA, glutamine and N-acetyl cysteine have been employed. All these nutrients may exert their effects by suppressing inflammation; n-3 PUFA by direct suppression of the process and glutamine and N-acetyl cysteine by acting indirectly on antioxidant status. Glutamine and nucleotides exert a direct effect on lymphocyte proliferation. Preliminary data suggests that not all genotypes are equally sensitive to the effects of immunonutrition. When further studies have been conducted to discern the precise interaction between each individual's genotype of relevance to the response to injury and infection, and immunonutrients, the level of precision in the application of immunonutrition will undoubtedly improve.

Modulation of pro-inflammatory cytokine biology by unsaturated fatty acids.

The production of pro-inflammatory cytokines, such as interleukins 1 and 6 and tumour necrosis factors, occurs rapidly following trauma or invasion of the body by pathogenic organisms. The cytokines mediate the wide range of symptoms associated with trauma and infection, such as fever, anorexia, tissue wasting, acute phase protein production and immunomodulation. In part, the symptoms result from a co-ordinated response, in which the immune system is activated and nutrients released, from endogenous sources, to provide substrate for the immune system. Although the cytokine mediated response is an essential part of the response to trauma and infection, excessive production of pro-inflammatory cytokines, or production of cytokines in the wrong biological context, are associated with mortality and pathology in a wide range of diseases, such as malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and AIDS. Cytokine biology can be modulated by antiinflammatory drugs, recombinant cytokine receptor antagonists and nutrients. Among the nutrients, fats have a large potential for modulating cytokine biology. A number of trials have demonstrated the anti-inflammatory effects of fish oils, which are rich in n-3 polyunsaturated fatty acids, in rheumatoid arthritis, inflammatory bowel disease, psoriasis and asthma. Animal studies, conducted by ourselves and others, indicate that a range of fats can modulate pro-inflammatory cytokine production and actions. In summary fats rich in n-6 polyunsaturated fatty acids enhance IL1 production and tissue responsiveness to cytokines, fats rich in n-3 polyunsaturated fatty acids have the opposite effect, monounsaturated fatty acids decrease tissue responsiveness to cytokines and IL6 production is enhanced by total unsaturated fatty acid intake. There are a large number of potential cellular mechanisms which may mediate the effects observed. The majority relate to the ability of fats to alter the composition of membrane phospholipids. As a consequence of alterations in phospholipid composition, membrane fluidity may change, altering binding of cytokines to receptors and G protein activity. The nature of substrate for various signalling pathways associated with cytokine production and actions may also be changed. Consequently, alterations in eicosanoid production and activation of protein kinase C may occur. We have examined a number of these potential mechanisms in peritoneal macrophages of rats fed fats with a wide range of fatty acid composition. We have found that the total C18:2 and 20:4 diacyl species of phosphatidylethanolamine in peritoneal macrophages relates in a positive curvilinear fashion with dietary linoleic acid intake; that TNF induced IL1 and IL6 production relate in a positive curvilinear fashion to linoleic acid intake; that leukotriene B4 production relates positively with dietary linoleic acid intake over a range of moderate intakes and is suppressed at high intakes, while PGE2 production is enhanced. There was no clear relationship between linoleic acid intake and membrane fluidity, however fluidity was influenced in a complex manner by the type of fat in the diet, the period over which the fat was fed and the presence of absence of TNF stimulation. None of the proposed mechanisms, acting alone, can explain the positive effect of dietary linoleic acid intake on pro-inflammatory cytokine production. However each may be involved, in part, in the modulatory effects observed.

Effect of antioxidative vitamins on immune function with clinical applications.

Infection and trauma cause inflammatory stress in patients. Tissue damage, enhanced inflammatory mediator production and suppressed lymphocyte function may occur as a consequence. The antioxidative vitamins, ascorbic acid and the tocopherols, are important not only for limiting tissue damage but also in preventing increased cytokine production which is a consequence of excessive activation of NF kappa B. Glutathione is a major endogenous antioxidant and is important for lymphocyte replication. Two vitamins, vitamin B6 and riboflavin participate in the maintainance of glutathione status. The former vitamin acts as a cofactor in the synthesis of cysteine (the rate limiting precursor for glutathione biosynthesis) and the latter vitamin is a cofactor for glutathione reductase. Deficiencies in tocopherol, vitamin B6 and riboflavin reduce cell numbers in lymphoid tissues of experimental animals and produce functional abnormalities in the cell mediated immune response. Ascorbic acid and tocopherols exert anti-inflammatory effects in studies in man and animals. In humans, dietary supplementation with ascorbic acid, tocopherols and vitamin B6 enhances a number of aspects of lymphocyte function. The effect is most apparent in the elderly.

The relationship between altered membrane composition, eicosanoids and TNF-induced IL1 and IL6 production in macrophages of rats fed fats of different unsaturated fatty acid composition.

The study investigated the changes in individual molecular species in PE and the effects of a variety of dietary fats with varying proportions of saturated and unsaturated fatty acids on membrane composition, eicosanoid production and cytokine production in thioglycollate-elicited rat macrophages. The data obtained indicates that the greatest degree of modulation by dietary fats on cytokine production was observed after 8 weeks feeding and at this time, the total diacyl species containing linoleic acid (18:2 n-6) and arachidonic acid (20:4 n-6) at the sn-2 position related in a curvilinear fashion to total 18:2 n-6 intake and that IL1 and IL6 production related in a curvilinear fashion to the total diacyl species with 20:4 and 18:2 at the sn-2 position. After 4 weeks of feeding, fish and olive oils enhanced production of IL6 and LTB4, however, while IL1 production, after 8 weeks of dietary treatment, was greatest from macrophages of animals fed corn and olive oils, PGE2 production was greatest in the former group and LTB4 production in the latter. Thus an eicosanoid effect may explain the modulatory influence of olive oil and IL1 production but, cannot explain the effect of corn oil on production of the cytokine. The data from the present study provides some insight into how dietary fats could provide therapy for conditions in which inflammatory cytokines are implicated.

Influence of dietary fats upon systolic blood pressure in the rat.

Studies were performed to determine whether feeding diets with differing fatty acid content and composition had an influence on systolic blood pressure in the rat. Weanling male rats were fed standard laboratory chow (2.9% fat in total), or synthetic diets (10% fat in total) containing fish oil, butter, coconut oil or corn oil, for 5 weeks. Coconut oil and butter diets were rich in saturated fatty acids, whilst fish oil and corn oil were rich in the n-3 and n-6 unsaturated fatty acids respectively. Systolic blood pressure was measured using an indirect tail-cuff method at the end of the feeding period, and compared to a group of weanling rats. Feeding the different diets did not alter the growth of the rats, so all animals were of similar weights at the time of blood pressure determination. Control (chow fed) animals, at nine weeks of age, had higher systolic blood pressures than the weanling, baseline control group. Fish oil fed rats had similar pressures to the chow fed rats. Corn oil fed rats had significantly lower systolic pressures than the controls. The rats led the diets rich in saturated fatty acids (butter and coconut oil) had significantly higher blood pressures than all other groups. Systolic blood pressure was found to be significantly related to the dietary intakes of saturated and unsaturated fatty acids. The dietary intake of linoleic acid was significantly higher in corn oil fed rats than in other groups. Systolic blood pressure was inversely related to linoleic acid intake. Feeding a diet rich in saturated fatty acids significantly increases blood pressure in the rat. A high intake of n-6 fatty acids, and in particular linoleic acid, appears to have a hypotensive effect. Prenatal exposure of the rats to a maternal low protein diet, abolished the hypertensive effects of the coconut oil diet and the hypotensive effect of the corn oil diet upon young adult females. The intrauterine environment may, therefore, be an important determinant of the effects of these fatty acids on blood pressure in later life.

Endotoxin induced production of interleukin-6 is enhanced by vitamin E deficiency and reduced by black tea extract.

Studies were performed to investigate the effect of a polyphenol rich extract from black tea and vitamin E on bacterial lipopolysaccharide (endotoxin) induced IL-6 production, alterations in liver glutathione and antioxidant acute phase protein (caeruloplasmin) concentration, in rats fed on a synthetic diet for 21 days. In the vitamin E sufficient group a significantly lower IL-6 concentration than in vitamin E deficient animals was observed. Addition of tea extract to the diet produced a similar reduction in IL-6, but no synergism occurred in the presence of both vitamin E and tea extract. However, a significantly lower caeruloplasmin and a significantly higher liver glutathione concentration was observed in rats fed both substances. It is suggested that consideration of dietary components which alter antioxidant/oxidant status may contribute towards treatment of inflammatory/autoimmune diseases.

Comparison of the modulatory influence of maize and olive oils and butter on metabolic responses to endotoxin in rats.

1. n-3 polyunsaturated fatty acids decrease responses to cytokines and inflammatory agents. The present study examines how different intakes of n-6 and n-9 fatty acids influence the metabolic response to endotoxin in Wistar rats. 2. Weanling male rats were, for 4 weeks, fed diets containing 50, 100 or 200 g/kg fat in the form of maize oil (rich in linoleic acid), butter (poor in linoleic acid, rich in oleic acid) or olive oil (adequate in linoleic acid, rich in oleic acid) or standard laboratory chow. All butter and olive oil diets included 10 g/kg maize oil, in total fat, to avoid essential fatty acid deficiency. 3. Rats subsequently received 800 micrograms/kg Escherichia coli endotoxin or sterile saline subcutaneously. Twenty-four hours after injection, the rate of tissue protein synthesis was measured in liver, lung, kidney, tibialis muscle and spleen by the 'flooding dose' method. Protein and zinc concentrations were assayed in all tissues and serum albumin and caeruloplasmin measured. 4. In animals fed chow, protein synthetic rate increased by 18%, 29% and 27% in liver, lung and kidney respectively. Tissue zinc concentrations increased by 33% in kidney, and tissue protein increased by 17%, 23% and 17% in liver, lung and kidney respectively. Serum caeruloplasmin increased by 60% and albumin concentration fell by 14%. 5. In animals consuming the 50 g/kg maize oil diet, protein synthetic rate increased by 56%, 36% and 34% in liver, lung and kidney respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Cysteine and methionine supplementation modulate the effect of tumor necrosis factor alpha on protein synthesis, glutathione and zinc concentration of liver and lung in rats fed a low protein diet.

The synthesis of cysteine-rich compounds such as glutathione and metallothionein is an integral part of the response to cytokines. To examine the essentiality of an adequate supply of sulfur amino acids during a response to tumor necrosis factor alpha (TNF) we fed rats a low protein (8% casein) diet supplemented with either cysteine and alanine, methionine and alanine, or alanine alone, or a normal protein (20% casein) diet for 8 d before injection with TNF or saline. Those animals injected with saline were pair-fed the intake of their TNF-injected counterparts for the 24 h after injection. In a second experiment, control groups fed the same diets but receiving no treatment were also examined to establish baseline values. Although few significant differences between the non-injected animals consuming food ad libitum were apparent, TNF injection and pair-feeding resulted in differences between the dietary groups. Supplementation of the low protein diet with either cysteine or methionine improved growth and increased liver and lung glutathione concentration, zinc concentration, protein concentration and protein synthesis compared with results for the alanine-supplemented group. Lung polymorphonuclear cells were proportionally elevated in the TNF-treated, alanine-supplemented group compared with the other dietary groups treated with TNF. The changes in protein synthesis and glutathione concentration of the liver in response to TNF showed that sulfur amino acids may be partitioned to a greater extent into hepatic protein than into glutathione when sulfur amino acid intake is low. Consequently the adequacy of dietary sulfur amino acids will determine the extent to which antioxidant defenses are maintained during inflammation.

Malnutrition and the immune response. 2. Impact of nutrients on cytokine biology in infection.

Interleukins 1 and 6 and tumour necrosis factor orchestrate a co-ordinated series of metabolic changes following invasions by pathogens. The changes are designed to destroy the pathogen. The response is characterized by fever, proteolysis in peripheral tissues, acute phase protein and antioxidant synthesis, and enhancement of the activity of the immune system. Cytokine production is enhanced by free radicals. Damage to the host may occur as a consequence. The deterious actions of these molecules are held in check by sophisticated antioxidant defences and systems which exert feedback control on cytokine biology. Nutrients have a profound effect upon the production and actions of cytokines. Protein energy malnutrition, dietary n-3 polyunsaturated fatty acids and vitamin E suppress cytokine production and actions. An opposite influence is exerted by n-6 polyunsaturated fatty acids, poor antioxidant defence, and supplementation of the diet with protein and branched chain amino acids. The synthesis of acute phase proteins and glutathione is dependent upon the adequacy of dietary sulphur amino acid intake. The consequences of the modulatory effects of previous and concurrent nutrient intake on cytokine biology are depletion of resources and damage to the host, which ranges from mild and temporary to severe, chronic or lethal.

Complex modulation of cytokine induction by endotoxin and tumour necrosis factor from peritoneal macrophages of rats by diets containing fats of different saturated, monounsaturated and polyunsaturated fatty acid composition.

1. Responses to cytokines and other inflammatory stimuli have been shown to be enhanced by fats rich in n-6 polyunsaturated fatty acids and suppressed by fats rich in n-3 polyunsaturated fatty acids and oleic acid or poor in n-6 polyunsaturated fatty acids. 2. Corn oil is rich and coconut oil, olive oil and butter are poor in n-6 polyunsaturated fatty acids. Olive oil and butter are rich in oleic acid. Fish oil is rich in n-3 polyunsaturated fatty acids. 3. The present study examines the effects of feeding standard chow or corn, coconut, fish and olive oils and butter for 4 and 8 weeks on subsequent cytokine production by peritoneal macrophages of rats. 4. Tumour necrosis factor production in response to a lipopolysaccharide stimulus and interleukin-1 and interleukin-6 production in response to a tumour necrosis factor challenge were studied. 5. All fats produced a small, but statistically insignificant, reduction in tumour necrosis factor production, which was greatest for olive oil at 8 weeks. 6. After 4 weeks, fish and olive oil significantly reduced interleukin-1 production. After 8 weeks, coconut oil suppressed production of the cytokine, and the inhibitory effect of fish oil was still apparent. After 8 weeks, corn and olive oil enhanced interleukin-1 production. 7. After 4 weeks of feeding, fish and olive oil enhanced interleukin-6 production. After 8 weeks, the enhancement by these fats increased, and corn oil and butter also enhanced production. Coconut oil produced no modulatory effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutritional antioxidants and the modulation of inflammation: theory and practice.

Highly potent substances are produced by the immune system. These substances include cytokines and oxidant molecules, such as hydrogen peroxide, free radicals, and hypochlorous acid. The purpose of immune cell products is to destroy invading organisms and damaged tissue, bringing about recovery. However, oxidants and cytokines can damage healthy tissue. Excessive or inappropriate production of these substances is associated with mortality and morbidity after infection and trauma, and in inflammatory diseases. Oxidants enhance interleukin-1, interleukin-8, and tumor necrosis factor production in response to inflammatory stimuli by activating the nuclear transcription factor, NF kappa B. Sophisticated antioxidant defenses directly and indirectly protect the host against the damaging influence of cytokines and oxidants. Indirect protection is afforded by antioxidants, which reduce activation of NF kappa B, thereby preventing up-regulation of cytokine production by oxidants. Cytokines increase both oxidant production and antioxidant defenses, thus minimizing damage to the host. While antioxidant defenses interact when a component is compromised, the nature and extent of the defenses are influenced by dietary intake of sulfur amino acids, for glutathione synthesis, and vitamins E and C. In animal studies, in vivo and in vitro responses to inflammatory stimuli are influenced by dietary intake of copper, zinc, selenium, N-acetylcysteine, cysteine, methionine, taurine, and vitamin E. Information from animal studies has yet to be fully translated into a clinical context. However, N-acetylcysteine, vitamin E, and a cocktail of antioxidant nutrients have reduced inflammatory symptoms in inflammatory joint disease, acute and chronic pancreatitis, and adult respiratory distress syndrome. Impaired antioxidant defenses may contribute to disease progression after infection with human immunodeficiency virus. Powerful arguments have been advanced for treatment with antioxidants to slow progression of acquired immunodeficiency syndrome.

Influence of butter and of corn, coconut and fish oils on the effects of recombinant human tumour necrosis factor-alpha in rats.

1. Tumour necrosis factor-alpha is produced in response to inflammatory stimuli. Fish oil can suppress the production and actions of cytokines. Little information is available on the effects of other fats on cytokine biology. We compared the effects of fats, with a wide range of fatty acid characteristics, on the effects of tumour necrosis factor-alpha on protein and zinc metabolism in rats. 2. Weanling rats were fed for 8 weeks on diets containing 10% fat in the form of corn, fish or coconut oils or butter before an intraperitoneal injection of recombinant human tumour necrosis factor-alpha was given. Measurements were made 24h after the injection. 3. In rats fed corn oil, food intake was reduced by 62% and rates of protein synthesis were increased by 86, 32 and 39% in the liver, lung and kidney, respectively. Zinc concentrations increased by 23% in the liver but decreased by 10% in the kidney. Plasma caeruloplasmin and complement C3 levels increased by 25% and 28%, respectively, and plasma albumin level decreased by 24%. 4. Fish oil prevented the increase in hepatic protein synthesis and changed the response of protein synthesis in lung and kidney to a decrease. Changes in hepatic and renal zinc concentrations were prevented. The response of the plasma caeruloplasmin level was unaltered but those of the plasma complement C3 and albumin concentrations were prevented. 5. Coconut oil and butter, although similarly low in linoleic acid, differed in their modulatory effects. With the exception of the rise in the plasma complement C3 concentration, all responses were prevented or greatly inhibited in rats fed butter.(ABSTRACT TRUNCATED AT 250 WORDS)

Cysteine and glycine supplementation modulate the metabolic response to tumor necrosis factor alpha in rats fed a low protein diet.

Responses to cytokines entail synthesis of substances rich in cysteine and glycine, such as glutathione (GSH), metallothionein and some plasma proteins. To examine the importance of an adequate supply of cysteine and glycine, we fed rats a low protein diet supplemented with L-cysteine and glycine, separately or in combination, or L-alanine, or a high protein diet for 1 wk before injection with tumor necrosis factor alpha (TNF) or saline. The high protein diet-fed group had greater liver weight and zinc and GSH concentrations after TNF than the group fed the low protein diet supplemented with alanine. Glycine and cysteine supplementation resulted in greater liver weight after TNF treatment than did alanine supplementation. Cysteine supplementation had a similar influence on GSH concentration. Ceruloplasmin, alpha-2-macroglobulin and alpha-1-acid glycoprotein were higher in TNF-treated rats than in saline controls in each dietary group. However, feeding supplementary glycine and cysteine and the high protein diet often resulted in different values than seen in animals fed the low protein diet supplemented with alanine. Paradoxically, lower ceruloplasmin concentrations were observed in animals fed the former diets than in those fed the latter. alpha-2-Macroglobulin concentration was lower in all animals fed low protein diets than in those fed the high protein diet. alpha-1-Acid glycoprotein was lowest in groups fed cysteine-supplemented diets and highest in the glycine-supplemented group.(ABSTRACT TRUNCATED AT 250 WORDS)

Taurine and serine supplementation modulates the metabolic response to tumor necrosis factor alpha in rats fed a low protein diet.

Plasma taurine and serine decrease following trauma and in severe inflammatory disease. These changes may signify an increase in requirements for sulfur amino acids. We previously demonstrated that cysteine supplementation can restore the impaired ability of rats fed an 8% casein diet to increase hepatic zinc, glutathione (GSH) and protein concentrations in response to tumor necrosis factor alpha (TNF alpha). Here we examined whether serine or taurine produces a similar effect, because serine provides the carbon skeleton of cysteine and taurine is its major metabolite. After 7 d of receiving either a 20% casein diet supplemented with cysteine or an 8% casein diet supplemented with alanine, serine or taurine, rats received an intraperitoneal injection of human TNF alpha. Tumor necrosis factor caused no change in hepatic GSH but resulted in a lower GSH concentration in lung in rats fed the alanine-supplemented diet. Neither taurine nor serine increased liver GSH relative to that in rats fed alanine, but the depression in lung due to TNF injection was lessened. The absolute increase in ceruloplasmin in response to TNF was enhanced in rats fed the alanine-supplemented diet relative to those fed the 20% casein diet. Serine normalized this response. This observation--the effects of taurine and serine on lung GSH and a significant negative correlation between ceruloplasmin and liver and lung GSH concentration in rats fed TNF--suggests that supplemental serine and taurine may improve antioxidant defenses when dietary supplies of cysteine are low but do not influence cysteine availability for a normal response to TNF.