Nutrient gene interactions and the inflammatory response

The function of inflammation is to combat pathogens following injury and surgery. During the inflammatory response, muscle and adipose tissue are catabolised to provide amino acids, glucose and fatty acids, for the immune response. The liver increases acute phase protein synthesis and anti-oxidant defences are enhanced by increased glutathione synthesis. Oxidants production creates a hostile environment for pathogens. The strength of the response is modulated by pro-inflammatory and anti-inflammatory cytokines. Interleukins (IL) 1 and 6 and tumour necrosis factor-? (TNF-?), fall into the first category, and IL-10 into the second. Neuroendocrine responses occur, and heat shock proteins are produced to curtail the inflammatory response. Inflammation exerts damaging and lethal effects. High production of IL-1 and TNF-? increases mortality in cerebral malaria, meningitis and sepsis. The ratio of pro- to anti-inflammatory cytokines also result in an adverse outcome to infection. High IL-6 to IL-10, and IL-10 to TNF ratios are associated with raised mortality. IL-1, IL-6 and TNF-? also play a damaging role in inflammatory disease and atheromatous plaque development. Genotype is a key factor which influences cytokine production and the strength of the inflammatory response. TNF-?, IL-1?, IL-6 and IL-10 production is strongly influenced by single nucleotide polymorphisms (SNPs) in the promoter region of the respective genes. Cytokine gene alleles are linked to increased morbidity in a range of diseases and conditions including sepsis, diabetes mellitus and cardiovascular disease. Studies on the anti-inflammatory effect of n-3 PUFAs indicate that individual genotype may influence the efficacy of immunonutrients in controlling inflammation. To improve patient outcome a better understanding is needed, of how nutrients, such as n-3 PUFAs can be used to control the inflammatory process and how individual genotype influences the response to such immunonutrients

The conditional role of inflammation in pregnancy and cancer

Cancer growth is characterized by proliferation of tumor cells in conjunction with invasion of all different immune cells that also invade healing wounds. This inflammatory response is necessary for cell proliferation but a second purpose of the inflammatory process is so that a low Th1/Th2 ratio is present with overexpression of IL-10, TGF-beta and IFN-gamma. Down regulation of NO activity also shifts the balance between M1 and M2 macrophages. Both aspects allow the antigenous nature of the tumor to escape anti-tumor effects of the host. Support for this view comes from observations in pregnancy in which the placenta exhibits identical immune responses and downregulation of NO production to allow trophoblast cells to invade the uterine tissues without being rejected. Cell proliferation requires a metabolic set-up in which the organism produces adequate substrate for growth. This also bears the characteristics of a systemic inflammatory response delivering a similar substrate mix required for cancer and fetal growth. This arrangement is clearly beneficial in pregnancy and therefore supports the view that cancer growth is facilitated by the organism: the cancerous tumor elicits an immunological response opposing anti-tumor effects and induces the host to produce building blocks for growth

Dangers, and benefits of the cytokine mediated response to injury and infection.

The inflammatory response is essential for survival in an environment where continuous exposure to noxious events threaten the integrity of the organism. However, the beneficial effects of the response are influenced by factors, which disadvantage individuals within a population. These factors include malnutrition, infection, genotype, gender, pre-existing inflammation, and chronic intoxication. Although the inflammatory response is generally successful in dealing with noxious events, life-long exposure to these events takes its toll on the integrity of the body and becomes apparent as chronic disease, atherosclerosis, organ failure, and frailty. Progress in ameliorating the consequences of lifetime exposure to inflammatory events can only occur if a fuller understanding can be obtained of the factors, which influence the persistence and outcome of the inflammatory response at an individual level. A multitude of studies has shown that specific nutrients, diets, and dietary restriction are able to modulate the inflammatory response in the population as a whole. To advance in this area, precise knowledge is needed of how the disadvantageous factors, mentioned above, affect the individual's response to anti-inflammatory nutrients

The effect of graded levels of dietary casein, with or without methionine supplementation, on glutathione concentration in unstressed and endotoxin-treated rats

Glutathione (GSH) concentration was measured in rats fed either graded levels of dietary casein (experiment 1; 180 g, 120 g, 80 g, or 60 g protein/kg diet) or graded levels of dietary casein, supplemented with methionine to equalize dietary sulfur amino acid content to that seen in an 180 g/kg casein diet supplemented with 0.3 g L-methionine/kg diet (experiment 2; 180 g protein +0.3 g L-methionine, 80 g protein +6.70 g L-methionine, or 60 g protein +7.45 g L-methionine/kg diet). Rats were given an inflammatory challenge by intraperitoneal injection of endotoxin (lipopolysaccharide from Escherichia coli), and were compared with ad libitum and pair-fed controls. Glutathione concentration in various organs (liver, lung, spleen, and thymus) decreased in animals fed the low-protein diets (80 g or 60 g/kg diet). Addition of the sulfur amino acid, methionine, to the low-protein diets restored glutathione concentrations in animals fed ad libitum and prevented the fall in GSH concentration, which occurred in lung, spleen, and thymus in response to the endotoxin. Despite the similarity in the amount of sulfur amino acid consumed between the groups fed the 180 g protein +0.3 g L-methionine and the 60 g protein +7.45 g L-methionine/kg diet, in experiment 2, hepatic GSH concentration significantly increased in the latter group, in animals fed ad libitum and in the endotoxin-treated animals, but not in the pair-fed controls

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.<br/