Showing papers by "Philip C. Calder published in 2002"

Polyunsaturated fatty acids, inflammation and immunity

Abstract: 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.

Dietary modification of inflammation with lipids

Abstract: The n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in high proportions in oily fish and fish oils. The n-3 PUFA are structurally and functionally distinct from the n-6 PUFA. Typically, human inflammatory cells contain high proportions of the n-6 PUFA arachidonic acid and low proportions of n-3 PUFA. The significance of this difference is that arachidonic acid is the precursor of 2-series prostaglandins and 4-series leukotrienes, which are highly-active mediators of inflammation. Feeding fish oil results in partial replacement of arachidonic acid in inflammatory cell membranes by EPA. This change leads to decreased production of arachidonic acid-derived mediators. This response alone is a potentially beneficial anti-inflammatory effect of n-3 PUFA. However, n-3 PUFA have a number of other effects which might occur downstream of altered eicosanoid production or might be independent of this activity. For example, animal and human studies have shown that dietary fish oil results in suppressed production of pro-inflammatory cytokines and can decrease adhesion molecule expression. These effects occur at the level of altered gene expression. This action might come about through antagonism of the effects of arachidonic acid-derived mediators or through more direct actions on the intracellular signalling pathways which lead to activation of transcription factors such as nuclear factor kappa B (NFB). Recent studies have shown that n-3 PUFA can down regulate the activity of the nuclear transcription factor NFB. Fish oil feeding has been shown to ameliorate the symptoms in some animal models of chronic inflammatory disease and to protect against the effects of endotoxin and similar inflammatory challenges. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some patients with asthma, supporting the idea that the n-3 PUFA in fish oil are anti-inflammatory. There are indications that inclusion of n-3 PUFA in enteral and parenteral formulas might be beneficial to patients in intensive care or post-surgery.

Fatty acids and lymphocyte functions.

Abstract: The immune system acts to protect the host against pathogenic invaders. However, components of the immune system can become dysregulated such that their activities are directed against host tissues, so causing damage. Lymphocytes are involved in both the beneficial and detrimental effects of the immune system. Both the level of fat and the types of fatty acid present in the diet can affect lymphocyte functions. The fatty acid composition of lymphocytes, and other immune cells, is altered according to the fatty acid composition of the diet and this alters the capacity of those cells to produce eicosanoids, such as prostaglandin E2, which are involved in immunoregulation. A high fat diet can impair lymphocyte function. Cell culture and animal feeding studies indicate that oleic, linoleic, conjugated linoleic, gamma-linolenic, dihomo-gamma-linolenic, arachidonic, alpha-linolenic, eicosapentaenoic and docosahexaenoic acids can all influence lymphocyte proliferation, the production of cytokines by lymphocytes, and natural killer cell activity. High intakes of some of these fatty acids are necessary to induce these effects. Among these fatty acids the long chain n-3 fatty acids, especially eicosapentaenoic acid, appear to be the most potent when included in the human diet. Although not all studies agree, it appears that fish oil, which contains eicosapentaenoic acid, down regulates the T-helper 1-type response which is associated with chronic inflammatory disease. There is evidence for beneficial effects of fish oil in such diseases; this evidence is strongest for rheumatoid arthritis. Since n-3 fatty acids also antagonise the production of inflammatory eicosanoid mediators from arachidonic acid, there is potential for benefit in asthma and related diseases. Recent evidence indicates that fish oil may be of benefit in some asthmatics but not others.

The immune system: a target for functional foods?

Abstract: The immune system acts to protect the host from infectious agents that exist in the environment (bacteria, viruses, fungi, parasites) and from other noxious insults. The immune system is constantly active, acting to discriminate ‘non-self’ from ‘self’. The immune system has two functional divisions: the innate and the acquired. Both components involve various blood-borne factors (complement, antibodies, cytokines) and cells. A number of methodologies exist to assess aspects of immune function; many of these rely upon studying cells in culture ex vivo. There are large inter-individual variations in many immune functions even among the healthy. Genetics, age, gender, smoking habits, habitual levels of exercise, alcohol consumption, diet, stage in the female menstrual cycle, stress, history of infections and vaccinations, and early life experiences are likely to be important contributors to the observed variation. While it is clear that individuals with immune responses significantly below ‘normal’ are more susceptible to infectious agents and exhibit increased infectious morbidity and mortality, it is not clear how the variation in immune function among healthy individuals relates to variation in susceptibility to infection. Nutrient status is an important factor contributing to immune competence: undernutrition impairs the immune system, suppressing immune functions that are fundamental to host protection. Undernutrition leading to impairment of immune function can be due to insufficient intake of energy and macronutrients and/or due to deficiencies in specific micronutrients. Often these occur in combination. Nutrients that have been demonstrated (in either animal or human studies) to be required for the immune system to function efficiently include essential amino acids, the essential fatty acid linoleic acid, vitamin A, folic acid, vitamin B6, vitamin B12, vitamin C, vitamin E, Zn, Cu, Fe and Se. Practically all forms of immunity may be affected by deficiencies in one or more of these nutrients. Animal and human studies have demonstrated that adding the deficient nutrient back to the diet can restore immune function and resistance to infection. Among the nutrients studied most in this regard are vitamin E and Zn. Increasing intakes of some nutrients above habitual and recommended levels can enhance some aspects of immune function. However, excess amounts of some nutrients also impair immune function. There is increasing evidence that probiotic bacteria improve host immune function. The effect of enhancing immune function on host resistance to infection in healthy individuals is not clear.

Nutrition and Immune Function

Abstract: Methods for studying interactions undernutrition fatty acids, inflammation and immunity chapters on major mineral elements and vitamins changes throughout thelife cycle public health policy. (Part contents).

Gene polymorphisms, inflammatory diseases and cancer

Abstract: Genes whose products play a critical role in regulation of the immune response include the human leucocyte antigen (HLA) and cytokine families of genes. The HLA genes are the most polymorphic found in the human genome, and the bulk of this polymorphism results in functional differences in expressed HLA molecules, resulting in inter-individual differences in presentation of peptide antigens to T-cells. In addition, a considerable number of cytokine-associated gene polymorphisms have been identified, the bulk of which occur in the upstream promoter sequences of these genes, which in many cases results in differential in vitro expression of the respective pro- or anti-inflammatory gene product. Particular HLA polymorphisms result in well-defined associations with a large number of immunologically-mediated diseases, including some diseases with known dietary risk factors. For example, individuals of HLA-DQA1*0501, DQB1*0201 genotype have a greater than 200-fold increased risk of developing intolerance to dietary wheat gluten (coeliac disease), and additional HLA-related factors may influence the development of malignant lymphoma within pre-existing coeliac disease. Similarly, HLA-DRB1 alleles sharing a common sequence motif constitute the primary known genetic risk factor for rheumatoid arthritis. The influence of polymorphisms associated with differential cytokine expression on disease susceptibility is currently of much interest. Most attention has been focused on associations with susceptibility to benign immunologically-mediated diseases, including a number of gut diseases. However, recent work from our laboratory indicates that cytokine polymorphisms may influence susceptibility to and prognosis in a number of different cancers, including malignant melanoma skin cancer and solid tumours which may be influenced by diet, such as prostate cancer (collaboration with the CRC/BPG UK Familial Prostate Cancer study). In addition, preliminary work suggests that dietary modulation of expression levels of certain cytokines in healthy human subjects may be genotype dependent.

Symposium on ’Nutrition in the post-genomic era’ Plenary session 4: Genetic variation and diet-related disease

Abstract: Re´sume´Parmi les ge`nes dont les produits jouent un rle critique dans la re´gulation de la re´ponse immune, on trouve les familles de ge`nes de l'antige`ne leucocyte humain (ALH) et de la cytokine. Les ge`nes ALH sont les plus polymorphes du ge´nome humain, et ce polymorphisme entraine des diffe´rences fonctionnelles des mole´cules ALH exprime´es, qui se traduit par des diffe´rences individuelles dans la manie`re dont des peptides antige´niques se pre´sentent aux cellules T. De plus, un nombre conside´rable de polymorphismes des ge`nes associe´s a la cytokine ont e´te´ identifie´s, la plupart d'entre eux se produisent au niveau du promoteur de ces ge`nes, ce que dans de nombreux cas se traduit par l'expression diffe´rentielle in vitro de leurs respectifs produits ge´ne´tiques pro- ou anti-inflammatoire. Des polymorphismes ALH particuliers aboutirent a` des associations bien de´finies avec un grand nombre de maladies immunologiquement medie´es, parmi lesquelles quelques-unes avec des facteurs de risque die´te´tique. Par exemple, des individus de ge´notype HLA-DQA1*0501, DQB1*0201 ont un risque deux cent fois plus grand de de´velopper une intole´rance au gluten alimentaire (maladie ce´liaque), et des facteurs additionnels en relation avec l'ALH peuvent influencer le de´veloppement d'un lymphome maligne dans une maladie ce´liaque existante. De mme, des alle`les HLA-DRB1 qui partage une se´quence motive commune constituent le premier facteur de risque ge´ne´tique de l'arthrite rhumatode. L'influence de polymorphismes associe´s a une expression de cytokine diffe´rentiel sur la susceptibilite´ aux maladies pre´sent dans ce moment un grand inte´rt. La plupart de l'attention a e´tait centre´ les associations avec la susceptibilite´ de maladies medie´es immunologiquement be´nignes, parmi eux un grand nombre de maladies de l'intestin. Toutefois, un travail re´cent dans notre laboratoire indique que les polymorphismes de la cytokine peuvent influencer la susceptibilite´ a` certains cancers (ainsi que son pronostic), entre eux le me´lanome de peau maligne et des tumeurs solides qui peuvent tre affecte´s par l'alimentation, comme le cancer de prostate (collaboration avec le CRC/BPG e´tude familial du cancer de prostate Royaume-Uni). De plus, des travails pre´liminaires sugge`rent que la modulation par l'alimentation des niveaux d'expression de certaines cytokines dans des sujets humains peut tre de´pendent du ge´notype.

The ability of fish oil to suppress tumor necrosis factor production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor

Abstract: Background: Tumor necrosis factor � (TNF-� ) mediates inflam- mation. High TNF-� production has adverse effects during dis- ease. Polymorphisms in the TNF-� and lymphotoxingenes influence TNF-� production. Fish oil suppresses TNF-� produc- tion and has variable antiinflammatory effects on disease. Objective: We examined the relation between TNF-� and lym- photoxingenotypes and the ability of dietary fish oil to suppress TNF-� production by peripheral blood mononuclear cells (PBMCs) in healthy men. Design: Polymorphisms in the TNF-� (TNF*1 and TNF*2) and lymphotoxin � (TNFB*1 and TNFB*2) genes were determined in 111 healthy young men. TNF-� production by endotoxin-stimulated PBMCs was measured before and 12 wk after dietary supplemen- tation with fish oil (6 g/d). Results: Homozygosity for TNFB*2 was 2.5 times more frequent in the highest than in the lowest tertile of inherent TNF-� pro- duction. The percentage of subjects in whom fish oil suppressed TNF-� production was lowest (22%) in the lowest tertile and dou- bled with each ascending tertile. In the highest and lowest tertiles, mean TNF-� production decreased by 43% (P < 0.05) and increased by 160% (P < 0.05), respectively. In the lowest tertile of TNF-� production, only TNFB*1/TNFB*2 heterozygous subjects were responsive to the suppressive effect of fish oil. In the middle tertile, this genotype was 6 times more frequent than the other lymphotoxingenotypes among responsive individuals. In the highest tertile, responsiveness to fish oil appeared unrelated to lymphotoxingenotype. Conclusion: The ability of fish oil to decrease TNF-� production is influenced by inherent TNF-� production and by polymor- phisms in the TNF-� and lymphotoxingenes. Am J Clin Nutr 2002;76:454-9.

Fatty acids and gene expression related to inflammation.

Abstract: form, parenteral administration of an emulsion containing soybean oil, medium-chain triglycerides (MCT), olive oil, fish oil and increased amounts of antioxidant vitamins and minerals to patients (n = 19) following major surgery enhanced ex vivo LTB5 production by leukocytes and decreased hospital stay (13.4 ± 2.0 vs. 20.4 ± 10.0 days) compared with standard soybean oil-based

Conjugated linoleic acid in humans--reasons to be cheerful?

Abstract: Conjugated linoleic acid (CLA) is a collective term used to describe the mixture of positional and geometric isomers of linoleic acid with conjugated double bonds (i.e. the two double bonds are separated by one single bond). The double bonds, each of which may be in the cis or trans con®guration, can be in any position of the carbon chain. Most frequently however, they are in positions 8 and 10, 9 and 11, 10 and 12, or 11 and 13. Most commercial preparations of CLA contain a mixture of isomers. The major sources of CLA in the human diet are meat and dairy products, particularly cheese. The amount of CLA present in dairy products varies according to the breed, feeding conditions and subsequent processing [1]. However, the major determinant appears to be the CLA content of the raw material and thus feeding, rather than processing, conditions determine the CLA content of foods [1]. Various strategies have been used for increasing the CLA content of cow's milk [1]. The predominant (490%) CLA in cow's milk is the cis-9, trans-11 isomer. Although rumen biohydrogenation of linoleic acid occurs via cis-9, trans-11 CLA, it appears that the majority of this CLA in cow's milk is produced within the mammary gland itself. The substrate for this is vaccenic acid (trans-11 octadecanoic acid) which is formed by rumen metabolism of cis-9, trans-11 CLA and then passes from the rumen to the mammary gland. Subsequently it is converted to cis-9, trans-11 CLA by the action of d9 desaturase.