Molecular Pathways Mediating Immunosuppression in Response to Prolonged Intensive Physical Training, Low-Energy Availability, and Intensive Weight Loss.

Exercise and exercise-induced weight loss have a beneficial effect on overall health, including positive effects on molecular pathways associated with immune function, especially in overweight individuals. The main aim of our study was to assess how energy deprivation (i.e., "semi-starvation") leading to substantial fat mass loss affects the immune system and immunosuppression in previously normal weight individuals. Thus, to address this hypothesis, we applied a high-throughput systems biology approach to better characterize potential key pathways associated with immune system modulation during intensive weight loss and subsequent weight regain. We examined 42 healthy female physique athletes (age 27.5 ± 4.0 years, body mass index 23.4 ± 1.7 kg/m2) volunteered into either a diet group (n = 25) or a control group (n = 17). For the diet group, the energy intake was reduced and exercise levels were increased to induce loss of fat mass that was subsequently regained during a recovery period. The control group was instructed to maintain their typical lifestyle, exercise levels, and energy intake at a constant level. For quantification of systems biology markers, fasting blood samples were drawn at three time points: baseline (PRE), at the end of the weight loss period (MID 21.1 ± 3.1 weeks after PRE), and at the end of the weight regain period (POST 18.4 ± 2.9 weeks after MID). In contrast to the control group, the diet group showed significant (false discovery rate <0.05) alteration of all measured immune function parameters-white blood cells (WBCs), immunoglobulin G glycome, leukocyte transcriptome, and cytokine profile. Integrative omics suggested effects on multiple levels of immune system as dysregulated hematopoiesis, suppressed immune cell proliferation, attenuated systemic inflammation, and loss of immune cell function by reduced antibody and chemokine secretion was implied after intense weight loss. During the weight regain period, the majority of the measured immune system parameters returned back to the baseline. In summary, this study elucidated a number of molecular pathways presumably explaining immunosuppression in individuals going through prolonged periods of intense training with low-energy availability. Our findings also reinforce the perception that the way in which weight loss is achieved (i.e., dietary restriction, exercise, or both) has a distinct effect on how the immune system is modulated.

Human breast milk and adipokines--A potential role for the soluble leptin receptor (sOb-R) in the regulation of infant energy intake and development.

Concentrations of different adipokines in human breast milk are thought to be able to affect energy intake of the infant. Leptin is a hormone synthesized by adipose tissue and the human placenta and favors satiety. The availability of leptin in breast milk is influenced by epithelial cells of the mammary gland that are known to be able to produce leptin, as well as leptin from maternal circulation that is transported to the breast milk, and which can thus in turn reach neonatal blood after absorption. Research so far as mainly focused on leptin concentrations in breast milk. However, evidence suggests that in addition to leptin concentrations levels of the so-called soluble leptin receptor (sOb-R), the main high-affinity binding protein for leptin in humans, are necessary in order to calculate the free leptin index (FLI) and to assess function of the leptin axis. FLI is calculated from the ratio of leptin to the sOb-R, and serves as the main parameter for assessing function of the leptin axis throughout maturation and development. Here we propose that assessing sOb-R levels in addition to leptin concentrations in breast milk could serve as a valuable tool to investigate effects of the leptin axis in breast milk because sOb-R concentrations can impact available leptin levels, and which in turn can have significant implications for infant energy intake and related development.

Downregulation of cellular protective factors of rumen epithelium in goats fed high energy diet.

Energy-rich diets can challenge metabolic and protective functions of the rumen epithelial cells, but the underlying factors are unclear. This study sought to evaluate proteomic changes of the rumen epithelium in goats fed a low, medium, or high energy diet. Expression of protein changes were compared by two-dimensional differential gel electrophoresis followed by protein identification with matrix assisted laser desorption ionisation tandem time-of-flight mass spectrometry. Of about 2,000 spots commonly detected in all gels, 64 spots were significantly regulated, which were traced back to 24 unique proteins. Interestingly, the expression profiles of several chaperone proteins with important cellular protective functions such as heat shock cognate 71 kDa protein, peroxiredoxin-6, serpin H1, protein disulfide-isomerase, and selenium-binding protein were collectively downregulated in response to high dietary energy supply. Similar regulation patterns were obtained for some other proteins involved in transport or metabolic functions. In contrast, metabolic enzymes like retinal dehydrogenase 1 and ATP synthase subunit beta, mitochondrial precursor were upregulated in response to high energy diet. Lower expressions of chaperone proteins in the rumen epithelial cells in response to high energy supply may suggest that these cells were less protected against the potentially harmful rumen toxic compounds, which might have consequences for rumen and systemic health. Our findings also suggest that energy-rich diets and the resulting acidotic insult may render rumen epithelial cells more vulnerable to cellular damage by attenuating their cell defense system, hence facilitating the impairment of rumen barrier function, typically observed in energy-rich fed ruminants.

Caloric restriction modifies both innate and adaptive immunity in the mouse small intestine

Although caloric restriction (CR) apparently has beneficial effects on the immune system, its effects on the immunological function of the intestinal mucosa are little known. The present study explored the effect of CR on the innate and adaptive intestinal immunity of mice. Balb/c mice were either fed ad libitum (control) or on alternate days fed ad libitum and fasted (caloric restriction). After 4 months, an evaluation was made of IgA levels in the ileum, the gene expression for IgA and its receptor (pIgR), as well as the expression of two antimicrobial enzymes (lysozyme and phospholipase A2) and several cytokines of the intestinal mucosa. CR increased the gene expression of lysozyme and phospholipase A2. The levels of IgA were diminished in the ileum, which apparently was a consequence of the reduced transport of IgA by pIgR. In ileum, CR increased the gene expression for most cytokines, both pro- and anti-inflammatory. Hence, CR differentially modified the expression of innate and adaptive immunity mediators in the intestine (AU)

Brain-immune interactions and the neural basis of disease-avoidant ingestive behaviour.

Neuro-immune interactions are widely manifested in animal physiology. Since immunity competes for energy with other physiological functions, it is subject to a circadian trade-off between other energy-demanding processes, such as neural activity, locomotion and thermoregulation. When immunity is challenged, this trade-off is tilted to an adaptive energy protecting and reallocation strategy that is identified as 'sickness behaviour'. We review diverse disease-avoidant behaviours in the context of ingestion, indicating that several adaptive advantages have been acquired by animals (including humans) during phylogenetic evolution and by ontogenetic experiences: (i) preventing waste of energy by reducing appetite and consequently foraging/hunting (illness anorexia), (ii) avoiding unnecessary danger by promoting safe environments (preventing disease encounter by olfactory cues and illness potentiation neophobia), (iii) help fighting against pathogenic threats (hyperthermia/somnolence), and (iv) by associative learning evading specific foods or environments signalling danger (conditioned taste avoidance/aversion) and/or at the same time preparing the body to counteract by anticipatory immune responses (conditioning immunomodulation). The neurobiology behind disease-avoidant ingestive behaviours is reviewed with special emphasis on the body energy balance (intake versus expenditure) and an evolutionary psychology perspective.

Dietary protein and energy supplies differentially affect resistance to parasites in lactating mammals.

Periparturient relaxation of immunity (PPRI) to parasites in mammals results in higher worm burden and worm egg excretion and may have a nutritional basis. Nippostrongylus brasiliensis re-infected lactating rats fed low-crude protein (CP) diets show an augmented degree of PPRI compared with their high CP-fed counterparts. However, such effects of CP scarcity have been confounded by metabolisable energy (ME) scarcity due to increased intake of the high-CP foods. Here, we independently assessed the effects of dietary CP and ME scarcity on the degree of PPRI. Second, parity rats were infected with N. brasiliensis larvae before mating. Upon parturition, dams were allocated to one of six feeding treatments (1-6), consisting of two levels of dietary ME supply, each with three levels of CP supply. On day 2 of lactation, dams were either re-infected with 1600 N. brasiliensis larvae or sham-infected with PBS, while litter size was standardised at ten pups. Dams and litters were weighed daily until either day 8 or 11 of lactation, when worm burdens were assessed as a proxy for PPRI. Increased CP and ME supply independently improved lactational performance. While ME supply did not affect parasitism, increasing CP supply reduced worm burden and the percentage of female worms in the small intestine; the latter was especially pronounced at the lower level of ME supply. The present results support the view that PPRI to parasites may be sensitive to CP scarcity, but not to moderate ME scarcity.

Breastfeeding's protection against illness-induced anorexia is mediated partially by docosahexaenoic acid.

OBJECTIVE: To test whether breastfeeding's protection against anorectic responses to infection is mediated by n-3 fatty acids' attenuation of interleukin (IL)-1beta and tumor necrosis factor (TNF)alpha. DESIGN: Experimental and observational studies. SETTING: A hospital-based study was conducted. SUBJECTS: Five groups of infants were followed; three in the experimental and two in the observational study. METHODS: Breast-fed- (BF-1), DHA-supplemented formula- (SFF-1), and non-DHA-supplemented formula-fed (FF-1) infants were studied before and after immunization against diphtheria, tetanus, pertussis and haemophilus influenzae type b. Pre- and post-immunization energy intakes (EI) and serum IL-1beta and TNFalpha were measured. The two other groups, breast-fed (BF-2) and formula-fed (FF-2) infants with pneumonia were followed throughout hospitalization. EI, IL-1beta and TNFalpha were measured at admission and discharge. Baseline erythrocyte fatty acid contents were determined. RESULTS: Both cytokines increased following immunization in all feeding groups. Post-immunization reductions in EI of SFF-1 infants (-11.8+/-5%, CI(95)=-23.3, 1.4%, P=0.07) were intermediate to those observed in BF-1 (-5.2+/-4.2%, CI(95)=-15.2, 5.9%, P=0.27) and FF-1 infants (-18+/-4.4%, CI(95)=-29%, -5.4%, P=0.02). In the observational study, TNFalpha (17.2+/-8.3 vs 3.4+/-3.0 ng/l, P=0.001) and decreases in EI (-31+/-43 vs -15+/-31%, CI(95)=-34%, 0.001%, P=0.056) were greater in FF-2 than in BF-2 infants at admission. Breastfeeding duration was associated positively with docosahexaenoic acid (DHA) erythrocyte contents, and negatively with admission TNFalpha. Decreases in EIs were associated with IL-1beta and TNFalpha concentrations. CONCLUSION: Reductions in EI following immunologic or infectious stimuli were associated with increases in IL-1beta and TNFalpha. Those reductions were attenuated by breastfeeding, and mediated in part by tissue DHA.

Dietary lipids in early development: relevance to obesity, immune and inflammatory disorders.

PURPOSE OF REVIEW: Regardless of social, cultural and behavioural environments, obesity is usually caused by an energy intake above requirements, which is accommodated by the accumulation of triacylglycerols. The composition of dietary fat impacts tissue fatty acids, which are important modulators of multiple cell functions, including differentiation, lipogenesis, lipolysis and the generation of inflammatory mediators. This review focuses on the possible contribution of fatty acids to the link between obesity and inflammation in young children. RECENT FINDINGS: Adipose tissue is a complex organ that functions to regulate fatty acid balance, clearing and releasing fatty acids, and synthesizing protein and signaling molecules that act as local and distant inflammatory mediators. Obesity, even in young children, is associated with increased circulating inflammatory mediators. As a result of changes in dietary fat compositions, infants are exposed to high n-6, saturated and trans fatty acids and low n-3 fatty acids. Saturated and trans fatty acids increase and n-3 fatty acids decrease many metabolic and inflammatory changes that accompany diet-induced triacylglycerol storage. High linoleic acid is associated with increased oxidative stress. SUMMARY: There is a biological reason to consider that dietary fatty acids may contribute to oxidative stress and heightened inflammatory responses in young children.

Combination of physical activity, nutrition, or other metabolic factors and vaccine response.

A number of lifestyle factors that reduce cancer risk in the primary prevention setting may be potential new targets for use in combination with cancer vaccines. This review discusses the modulation of energy balance (physical activity, calorie restriction, and obesity prevention), and the supplementation with natural and synthetic analogs of vitamins A and E, as potential interventions for use in combination with cancer vaccines. Additionally, the pharmacologic manipulation of nutrient metabolism in the tumor microenvironment (e.g., arachidonic acid, arginine, tryptophan, and glucose metabolism) is discussed. This review includes a brief overview of the role of each agent in primary cancer prevention; outlines the effects of these agents on immune function, specifically adaptive and/or anti-tumor immune mechanisms, when known; and discusses the potential use of these interventions in combination with therapeutic cancer vaccines. Modulation of energy balance through exercise and strategies targeting nutrient metabolism in the tumor microenvironment represent the most promising interventions to partner with therapeutic cancer vaccines. Additionally, the use of vitamin E succinate and the retinoid X receptor-directed rexinoids in combination with cancer vaccines offer promise. In summary, a number of energy balance- and nutrition-related interventions are viable candidates for further study in combination with cancer vaccines.

Effect of polydextrose on intestinal microbes and immune functions in pigs.

Dietary fibre has been proposed to decrease risk for colon cancer by altering the composition of intestinal microbes or their activity. In the present study, the changes in intestinal microbiota and its activity, and immunological characteristics, such as cyclo-oxygenase (COX)-2 gene expression in mucosa, in pigs fed with a high-energy-density diet, with and without supplementation of a soluble fibre (polydextrose; PDX) (30 g/d) were assessed in different intestinal compartments. PDX was gradually fermented throughout the intestine, and was still present in the distal colon. Irrespective of the diet throughout the intestine, of the four microbial groups determined by fluorescent in situ hybridisation, lactobacilli were found to be dominating, followed by clostridia and Bacteroides. Bifidobacteria represented a minority of the total intestinal microbiota. The numbers of bacteria increased approximately ten-fold from the distal small intestine to the distal colon. Concomitantly, also concentrations of SCFA and biogenic amines increased in the large intestine. In contrast, concentrations of luminal IgA decreased distally but the expression of mucosal COX-2 had a tendency to increase in the mucosa towards the distal colon. Addition of PDX to the diet significantly changed the fermentation endproducts, especially in the distal colon, whereas effects on bacterial composition were rather minor. There was a reduction in concentrations of SCFA and tryptamine, and an increase in concentrations of spermidine in the colon upon PDX supplementation. Furthermore, PDX tended to decrease the expression of mucosal COX-2, therefore possibly reducing the risk of developing colon cancer-promoting conditions in the distal intestine.

Energy restriction with different protein quantities and source: implications for innate immunity.

OBJECTIVE: Physical age, energy restriction (ER), and weight loss have been reported to suppress indices of innate immunity, which may increase the risk of illness. To evaluate these interactions, we recruited older, postmenopausal women (50 to 80 years) to fill one of the following 9-week ER (1250 kcal/d) groups: beef [n = 14; reported intakes 46% carbohydrate (CHO):24% protein (PRO):30% fat], chicken (n = 15; 51% CHO:25% PRO:24% fat), or CHO (n = 14; 59% CHO:17% PRO:24% fat), or a non-intervention control (n = 11). RESEARCH METHODS AND PROCEDURES: Fasting blood was collected before and after ER to determine leukocyte phenotype, neutrophil oxidative burst capacity, natural killer cell activity, stimulated interleukin-2 and interferon-gamma production, and blood zinc and iron concentrations. RESULTS: No significant effects of ER (8.6% weight loss) or PRO quantity and source were found for the majority of indices of innate immunity. Small but significant (p < 0.05) declines in interleukin-2 production were found in the chicken and CHO groups only; however, the clinical significance of this finding is not known. DISCUSSION: In the present study, 9 weeks of moderate ER did not suppress immunity in postmenopausal women. Also, contrary to our hypothesis, differential zinc and iron intakes did not significantly alter immunity.

Effect of nutritional status and fat reserves on the periparturient immune response to Haemonchus contortus infection in sheep.

A study was made of the effect of body fat stored by ewes in early pregnancy on the subsequent immune response to gastrointestinal parasites around parturition. Pregnant ewes were given access to a lucerne pelleted diet either ad libitum (H) or at approximately 0.70 of their maintenance requirements (L) from the 42nd day of pregnancy in order to achieve a clearly differentiated level of body reserves by the 90th day of pregnancy. Then, all animals were put on the same plane of nutrition till 3 weeks after parturition. All ewes in both groups received 7,000 infective larvae of Haemonchus contortus per week for 7 weeks prior to lambing. The dietary treatments led to large differences between both groups of ewes in back-fat thickness that had a high correlation with mean plasma concentrations of leptin. In spite of the fact that animals were on the same plane of nutrition at infection time, host resistance, as measured by faecal egg counts, was significantly affected by the nutritional treatment established during early pregnancy. This effect produced noticeable differences in worm size and in worm burden at lambing. The response was accompanied by a marked increase in circulating eosinophils in better-fed ewes than in those maintained on a restricted diet in early pregnancy. Serum pepsinogen concentration, however, was inversely affected by the nutritional treatment till lambing, showing a maximum difference as early as 2 weeks after infection. The results support the view that higher levels of nutrition during early pregnancy enhance the expression of immunity against gastrointestinal parasites around parturition. Furthermore, the differences in the immune response appeared associated with serum leptin levels suggesting that leptin may be a key link between nutritional status and the protective immune reactivity against GI nematode infection.

Efficacy of immunologic assays for the detection of Johne's disease in dairy cows fed additional energy during the periparturient period.

This study was designed to evaluate if the immunosuppression typically observed during the immediate periparturient period (3 weeks before and after calving) in dairy cows influences the effectiveness of diagnostic tests for the detection of Johne's disease; and, if providing additional energy to the cows during this period would minimize any immunosuppressive effects. Twelve dairy cows naturally infected with Mycobacterium paratuberculosis were fitted with rumen cannulas in late gestation and assigned to treatment groups: control, n = 6; or stuffed, n = 6. Cows in the control group were allowed to consume feed ad libitum. Cows assigned to the stuffed treatment group were also fed ad libitum but received additional total mixed ration by manually stuffing their rumens with refused feed to maintain a dry matter intake of 2% body weight/day before calving and 2.5% body weight/day after calving. Parturition had a significant impact on immune function with significant reductions in M. paratuberculosis-specific antibodies detected in the serum and milk regardless of treatment group. Similarly, in vitro immunoglobulin production was decreased at calving for both treatment groups. In addition, stuffing cows modulated cell-mediated immune function by reducing antigen-specific lymphocyte proliferation and interferon-gamma production after calving. Shedding of M. paratuberculosis in the milk was apparent in 58% (7/12) of cows after parturition with no difference noted between control and stuffed animals. Parturition had no major effect on fecal shedding of cows regardless of treatment. These data suggest that parturition had a significant effect on immune function parameters including diagnostic tests for paratuberculosis. Furthermore, providing additional energy to cows with Johne's disease did not preclude immunosuppressive effects during the periparturient period.

Dairy products, meat and sports performance.

Creatine supplementation improves repetitive, short-term performance. It has not been shown that exclusion of meat from the diet would impair repetitive short-term performance. In contrast, reduction of protein intake and a concomitant increase of carbohydrate intake during a period of 3-5 days improves anaerobic (2-7 minutes) performance. The protein intake in a mixed or lacto-vegetarian diet is adequate even for elite athletes, providing that energy requirements are met. Many dietary supplements have been suggested to increase muscle mass and/or to decrease fat mass. Although the effects of conjugated linoleic acid on body composition in athletes are not clear, some positive findings in untrained, obese individuals call for more studies. Strenuous training may impair immune function and increase the susceptibility to infections. Exclusion of meat from the diet does not seem to have adverse effects on immune function. Glutamine supplementation (>3-6 g/day) may improve immune function, but more studies are needed. Similarly, more studies on the possible effects of whey protein and probiotic supplementation on immune function and performance in physically highly active individuals are warranted. Vitamin and mineral balance are not usually a problem among athletes. Notable exceptions may be calcium and iron in some females. Increased calcium intake in athletes with hormonal and menstrual disturbances could theoretically help in maintaining bone status; however, no data are available. A diet with meat may help in maintaining adequate iron stores.

Breastfeeding attenuates reductions in energy intake induced by a mild immunologic stimulus represented by DPTH immunization: possible roles of interleukin-1beta, tumor necrosis factor-alpha and leptin.

An attenuated severity of infections is among the well-documented benefits of breast-feeding. The degree to which this attenuated severity extends to the amelioration of anorexia is understood incompletely, and possible underlying mechanisms have received limited evaluation. This study was designed to test whether breast-feeding attenuates reductions in energy intake associated with a mild immunologic stimulus and to assess poststimulus relationships among putative reductions in energy intake and serum interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and leptin concentrations. A quasi-experimental, hospital-based study was conducted in 23 healthy fully breast- (BF) and formula-fed (FF) infants who received the quadruple diphtheria, pertussis, tetanus and hemophilus influenza (DPTH) immunization as an immunologic challenge. Only FF infants had decreased energy intakes (12 +/- 2%, P = 0.001) after immunization. Leptin concentrations increased after immunization only in FF infants (30 +/- 7%, P = 0.03). Correlations between postimmunization increases in IL-beta and reductions in energy intake were of borderline significance (r = -0.56, P = 0.08). These findings support the view that breast-feeding protects against anorectic responses to mild immunologic stimuli. Increases in leptin are associated with reductions in energy consumption in the postimmunization period in FF infants and postimmunization changes in IL-1beta concentrations likely are related to reductions in energy intake in response to immunologic stimuli.

Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury.

The life-prolonging effects of calorie restriction (CR) may be due to reduced damage from cumulative oxidative stress. Our goal was to determine the long-term effects of moderate dietary CR on the myocardial response to reperfusion after a single episode of sublethal ischemia. Male Fisher 344 rats were fed either an ad libitum (AL) or CR (40% less calories) diet. At age 12 mo the animals were anaesthetized and subjected to thoracotomy and a 15-min left-anterior descending coronary artery occlusion. The hearts were reperfused for various periods. GSH and GSSG levels, nuclear factor-kappaB (NF-kappaB) DNA binding activity, cytokine, and antioxidant enzyme expression were assessed in the ischemic zones. Sham-operated animals served as controls. Compared with the AL diet, chronic CR limited oxidative stress as seen by rapid recovery in GSH levels in previously ischemic myocardium. CR reduced DNA binding activity of NF-kappaB. The kappaB-responsive cytokines interleukin-1beta and tumor necrosis factor-alpha were transiently expressed in the CR group but persisted longer in the AL group. Furthermore, expression of manganese superoxide dismutase, a key antioxidant enzyme, was significantly delayed in the AL group. Collectively these data indicate that CR significantly attenuates myocardial oxidative stress and the postischemic inflammatory response.

Calorie restriction increases Fas/Fas-ligand expression and apoptosis in murine splenic lymphocytes.

One-month-old male ICR mice were fed a nutritionally adequate, semipurified diet, either ad libitum (AL) or calorie restricted (CR) (40% less food) for 6 months and were killed to obtain spleens. Flow cytometric analysis revealed increased proportions of both CD4+ and CD8+ T cells in CR-fed mice compared to AL-fed mice. The T cell subsets of CR-fed mice were also found to have higher levels of plasma membrane Fas receptor expression. Similarly, Fas-ligand (Fas-L) expression was higher in anti-CD3-stimulated CD4+ and CD8+ T cells. CR-fed mice also had increased numbers of annexin V-positive CD4+ and CD8+ T cells in stimulated splenic lymphocytes suggesting an increased potential for apoptosis. Fas and Fas-L gene expression in splenic lymphocytes, which correlated closely with the observed increased rate of apoptosis, was significantly increased in CR-fed mice compared to AL-fed mice. In conclusion, these results indicate that CR increases the expression of Fas and Fas-L which may contribute to the known beneficial effects of CR such as prolongation of life span by activating chronic physiologically mediated apoptosis.

The increase in the induction of IL-2 expression with caloric restriction is correlated to changes in the transcription factor NFAT.

The objective of this study was to determine if the increase in the induction of interleukin-2 (IL-2) expression with caloric restriction correlates with changes in binding activity of the IL-2-specific transcription factor NFAT (nuclear factor of activated T cells) and/or the ubiquitous transcription factor AP-1 in T cells from male Fischer 344 rats. Splenic T cells were isolated from young (6-month) and old (24-month) rats fed ad libitum and from old (24-month) rats fed a restricted diet (40% caloric restriction) that began at 6 weeks of age. T cells were stimulated with concanavalin A (Con A) and the expression of IL-2 and the DNA binding activity of the transcription factors NFAT and AP-1 were measured in these cells. We found that the induction of IL-2 activity and mRNA levels decreased with age and that caloric restriction significantly (P < 0.05) reduced the age-related decline in IL-2 expression. The ability of nuclear extracts from T cells isolated from old rats fed ad libitum and restricted old rats to bind to the NFAT oligonucleotide or AP-1 oligonucleotide decreased with age. Caloric restriction significantly (P < 0.05) reduced the age-related decline in NFAT but had no significant effect on AP-1 binding activity. We also measured the induction of c-fos and c-jun expression by Con A in T cells from young and old rats fed ad libitum or caloric-restricted diet. The induction of c-fos protein and mRNA levels but not c-jun protein or mRNA levels decreased significantly with age. Caloric restriction significantly (P < 0.05) reduced the age-related decline in c-fos expression but had no significant effect on c-jun expression. Therefore, the increase in IL-2 expression with caloric restriction correlates with an increase in binding activity of transcription factor NFAT and an increase in the expression of c-fos, which is a component of the NFAT-protein complex.

Effects of food restriction in military training on T-lymphocyte responses.

In a stress model which included food restriction, we examined the effects of physically rigorous military training and increased caloric intake on T-lymphocyte responses and lymphocyte subsets. T-lymphocyte proliferation and release of soluble receptor for interleukin-2 (slL-2R) in vitro were measured in two separate training classes of male U.S. Army ranger course (RC) trainees at the start and during the RC. Trainees in group 1 (n = 55) and 2(n = 50), respectively, had mean (+/- SD) energy intakes of 11.8 +/- 7.0 and 13.6 +/- 6.7 MJ/d, averaged total daily energy expenditures of 16.7 and 17.6 MJ/d, and experienced body weight losses of 15.]% and 12.6%. Both groups showed decreases T-lymphocyte responses in vitro: proliferation to phytohemagglutinin (PHA) and tetanus toxoid (TT), and released slL-2R to PHA. Group 2 with an intended 15% increase in energy during the RC over group 1 showed 22% and 26% less severe suppressions of T-lymphocyte proliferation and released slL-2R, respectively, in vitro. Group 2 also showed that short-term (9 days) removal of the food restriction stressor allowed for corrected body weight, total lymphocyte and T-lymphocyte subset counts but not suppressed T-lymphocyte responses in vitro. These results demonstrate that soldiers in physically rigorous military training are at risk of suppressed T-lymphocyte immunocompetence, and this is greater if they also experience inadequate energy intake.

The effect of strenuous exercise, calorie deficiency and sleep deprivation on white blood cells, plasma immunoglobulins and cytokines.

Moderate exercise appears to stimulate the immune system, but there is good evidence that intense exercise can cause immune deficiency. In the present study the authors examined the effect of continuous physical exercise (35% of VO2 max), calorie deficiency and sleep deprivation on the immune system of young men participating in a 5-7 days military training course. There was a two-three fold increase of neutrophils from day 1, the values remained high and decreased slightly at the end of the course. Monocyte counts also increased with a pattern similar to that of neutrophils. Eosinophils decreased to 30% of control and lymphocyte numbers decreased by 30-40%. All the major subgroups (CD4 T cells, CD8 T cells, B cells, NK cells) were reduced. Neutrophil function, as tested by measuring chemotaxis, was significantly stimulated during the first days of the course, in particular in the group with the lowest calorie intake. The mitogenic response of lymphocytes to PHA and Con A was variable, ranging from stimulation during one course to no effect in another course. Serum levels of immunoglobulins decreased significantly during the course. IgG was reduced by 6-7%, IgA by 10-20% and IgM by 20-35%. The authors found no changes of interleukin 1, 2 and 4 during the course, but a (12-20%) reduction (P less than 0.01) of interleukin 6, and an increase (P less than 0.01) of granulocyte-macrophage colony stimulating factor. Altogether the results from the ranger course present a mixed-up picture. The non-specific phagocyte-related immunity was enhanced. On the other hand, the data indicate that even a moderate physical activity, around the clock, caused significant suppression of a number of parameters reflecting the status of the specific, lymphocyte-related immunity. It is noteworthy, however, that there was no significantly increased infection rate during the course or in the first 4-5 weeks thereafter.