The impact of acute and chronic stress on the hypothalamic-pituitary-adrenal (HPA) axis is reviewed and evidence presented that corticotrophin releasing factor (CRF) is the stress neurotransmitter which plays an important role in the activation of the central sympathetic and serotonergic systems. The activity of CRF is expressed through specific receptors (CRF 1 and 2) that are antagonistic in their actions and widely distributed in the limbic regions of the brain, as well as in the hypothalamus, and on immune cells.

The mechanism whereby chronic stress, via the CRF induced activation of the dorsal raphe nucleus, can induce a change in the serotonergic system, involves an increase in the 5HT2A and a decrease in the 5HT1A receptor mediated function. Such changes contribute to the onset of anxiety and depression. In addition, the hypersecretion of glucocorticoids that is associated with chronic stress and depression desensitises the central glucocorticoid receptors to the negative feedback inhibition of the HPA axis. This indirectly results in the further activation of the HPA axis.

The rise in pro-inflammatory cytokines that usually accompanies the chronic stress response results in a further stimulation of the HPA axis thereby adding to the stress response. While CRF would appear to play a pivotal role, evidence is provided that simultaneous changes in the serotonergic and noradrenergic systems, combined with the activation of peripheral and central macrophages that increase the pro-inflammatory cytokine concentrations in the brain and blood, also play a critical role in predisposing to anxiety and depression. Neurodegenerative changes in the brain that frequently occur in the elderly patient with major depression, could result from the activation of indoleaminedioxygenase (IDO), a widely distributed enzyme that converts tryptophan via the kynenine pathway to for the neurotoxic end product quinolinic acid.

Pro-inflammatory cytokines are critical in mechanisms of muscle atrophy. In addition, asparagine (Asn) is necessary for protein synthesis in mammalian cells. We hypothesised that Asn could attenuate lipopolysaccharide (LPS)-induced muscle atrophy in a piglet model. Piglets were allotted to four treatments (non-challenged control, LPS-challenged control, LPS+0·5 % Asn and LPS+1·0 % Asn). On day 21, the piglets were injected with LPS or saline. At 4 h post injection, piglet blood and muscle samples were collected. Asn increased protein and RNA content in muscles, and decreased mRNA expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1). However, Asn had no effect on the protein abundance of MAFbx and MuRF1. In addition, Asn decreased muscle AMP-activated protein kinase (AMPK) α phosphorylation, but increased muscle protein kinase B (Akt) and Forkhead Box O (FOXO) 1 phosphorylation. Moreover, Asn decreased the concentrations of TNF-α, cortisol and glucagon in plasma, and TNF-α mRNA expression in muscles. Finally, Asn decreased mRNA abundance of muscle toll-like receptor (TLR) 4 and nucleotide-binding oligomerisation domain protein (NOD) signalling-related genes, and regulated their negative regulators. The beneficial effects of Asn on muscle atrophy may be associated with the following: (1) inhibiting muscle protein degradation via activating Akt and inactivating AMPKα and FOXO1; and (2) decreasing the expression of muscle pro-inflammatory cytokines via inhibiting TLR4 and NOD signalling pathways by modulation of their negative regulators.

The study evaluated whether feeding diosmectite–ZnO composite (DS-ZnO) at 500 mg Zn/kg to early weaned pigs would alleviate the weaning-related intestinal disorders as a substitute for high concentration of ZnO (2250 mg Zn/kg). The pigs weaned at an age of 21 ± 1 d were allotted to four treatments groups as follows: (1) control; (2) DS-ZnO, 500 mg Zn/kg diet; (3) ZnO, 2250 mg Zn/kg diet; and (4) mixture of 2·0 g DS/kg and 500 mg Zn/kg from ZnO (equal amount of DS and ZnO in the DS-ZnO treatment group). The results showed that, compared with the control on days 7 and 14 post-weaning, addition of DS-ZnO at 500 mg Zn/kg improved (P< 0·05) daily gain and feed intake, decreased (P< 0·05) post-weaning scour scores, increased (P< 0·05) jejunal villus height and the ratio of villus height and crypt depth, decreased (P< 0·05) jejunal paracellular permeability of fluorescein isothiocyanate dextran 4 kDa and up-regulated (P< 0·05) tight junction protein expression of occludin, claudin-1 and zonula occludens-1 in jejunal mucosa. The mRNA levels of TNF-α, IL-6 and interferon-γ (IFN-γ) on day 7 post-weaning were also decreased (P< 0·05). The piglets fed DS-ZnO at 500 mg Zn/kg did not differ in the above parameters from those fed ZnO at 2250 mg Zn/kg, while they had better performance than those fed the mixture of DS and ZnO. Supplementation with DS-ZnO at 500 mg Zn/kg was effective in alleviating diarrhoea, barrier dysfunction and inflammatory cytokine expression and up-regulating tight junction protein expression.

β-Glucans have been identified as natural biomolecules with immunomodulatory activity. The first objective of the present study was to compare the effects of purified β-glucans derived from Laminariadigitata, L. hyperborea and Saccharomyces cerevisiae on piglet performance, selected bacterial populations and intestinal volatile fatty acid (VFA) production. The second aim was to compare the gene expression profiles of the markers of pro- and anti-inflammation in both unchallenged and lipopolysaccharide (LPS)-challenged ileal and colonic tissues. β-Glucans were included at 250 mg/kg in the diets. The β-glucans derived from L. hyperborea, L. digitata and S. cerevisiae all reduced the Enterobacteriaceae population (P < 0·05) without influencing the lactobacilli and bifidobacteria populations (P>0·05) in the ileum and colon. There was a significant interaction between gastrointestinal region and β-glucan source in the expression of cytokine markers, IL-1α (P < 0·001), IL-10 (P < 0·05), TNF-α (P < 0·05) and IL-17A (P < 0·001). β-Glucans did not stimulate any pro- or anti-inflammatory cytokine markers in the ileal epithelial cells. In contrast, the expression of a panel of pro- and anti-inflammatory cytokines (IL-1α, IL-10, TNF-α and IL-17A) was down-regulated in the colon following exposure to β-glucans from all the three sources. However, the data suggest that the soluble β-glucans derived from L. digitata may be acting via a different mechanism from the insoluble β-glucans derived from L. hyperborea and S. cerevisiae, as the VFA profile was different in the L. digitata-treated animals. There was an increase in IL-8 gene expression (P < 0·05) in the gastrointestinal tract from the animals exposed to L. digitata following an LPS ex vivo challenge that was not evident in the other two treatment groups. In conclusion, β-glucans from both seaweed and yeast sources reduce Enterobacteriaceae counts and pro-inflammatory markers in the colon, though the mechanisms of action may be different between the soluble and insoluble fibre sources.

Regular consumption of fruit and vegetables may be associated with decreased CVD risk. In the present study, we investigated the effects of blackcurrant (BC) juice, rich in polyphenols and ascorbic acid, on oxidative and inflammatory biomarkers in cultured macrophages in vitro and in human subjects with an atherosclerosis-prone phenotype (after consumption of a high-energy meal). In cultured macrophages (RAW264.7), BC treatment significantly inhibited lipopolysaccharide-induced inflammation as indicated by lower mRNA levels of TNF-α, IL-1β and inducible NO synthase (iNOS) and lower nuclear p65 levels indicating decreased NF-κB activity. iNOS protein levels were lower and haem oxygenase 1 levels higher in BC-treated cells when compared with untreated controls. Subjects given a high-energy meal had elevated serum glucose and insulin levels with no significant difference between the BC-based juice and placebo treatment groups. TAG following meal ingestion tended to be attenuated after the BC treatment. Plasma ascorbic acid and radical-scavenging capacity were decreased following placebo meal consumption; however, BC significantly elevated both parameters compared with baseline and placebo ingestion. Plasma oxidised LDL, α-tocopherol and paraoxonase activity were unchanged in both treatment groups. Furthermore, production of TNF-α and IL-1β was not significantly changed by BC meal consumption. The present results suggest potential antioxidative and anti-inflammatory properties of BC in vitro in cultured macrophages. Although the observations were not directly transferable to a postprandial in vivo situation, the present results show that BC juice consumption may improve postprandial antioxidant status as indicated by higher ascorbic acid levels and free radical-scavenging capacity in plasma.

This study evaluated whether arginine (Arg) supplementation could attenuate gut injury induced by Escherichia coli lipopolysaccharide (LPS) challenge through an anti-inflammatory role in weaned pigs. Pigs were allotted to four treatments including: (1) non-challenged control; (2) LPS-challenged control; (3) LPS+0·5 % Arg; (4) LPS+1·0 % Arg. On day 16, pigs were injected with LPS or sterile saline. At 6 h post-injection, pigs were killed for evaluation of small intestinal morphology and intestinal gene expression. Within 48 h of challenge, 0·5 % Arg alleviated the weight loss induced by LPS challenge (P = 0·025). In all three intestinal segments, 0·5 or 1·0 % Arg mitigated intestinal morphology impairment (e.g. lower villus height and higher crypt depth) induced by LPS challenge (P < 0·05), and alleviated the decrease of crypt cell proliferation and the increase of villus cell apoptosis after LPS challenge (P < 0·01). The 0·5 % Arg prevented the elevation of jejunal IL-6 mRNA abundance (P = 0·082), and jejunal (P = 0·030) and ileal (P = 0·039) TNF-α mRNA abundance induced by LPS challenge. The 1·0 % Arg alleviated the elevation of jejunal IL-6 mRNA abundance (P = 0·053) and jejunal TNF-α mRNA abundance (P = 0·003) induced by LPS challenge. The 0·5 % Arg increased PPARγ mRNA abundance in all three intestinal segments (P < 0·10), and 1·0 % Arg increased duodenal PPARγ mRNA abundance (P = 0·094). These results indicate that Arg supplementation has beneficial effects in alleviating gut mucosal injury induced by LPS challenge. Additionally, it is possible that the protective effects of Arg on the intestine are associated with decreasing the expression of intestinal pro-inflammatory cytokines through activating PPARγ expression.

The study was conducted to investigate the effects of different oils on growth performance and immune responses of chickens after challenge with lipopolysaccharide (LPS). A total of 288 chickens were assigned in a 2 × 2 factorial design. Factors were dietary fat type (4.5% maize oil or 4.5% fish oil) and immunological challenge (LPS or saline). At 20 days and 27 days of age, chickens were injected intraperitoneally with either 1 mg/kg body weight of LPS or sterile saline. LPS decreased feed intake from 21 days to 28 days of age and body-weight gain from 21 days to 42 days of age. Fish oil improved feed-conversion efficiency of chickens after LPS challenge for the first time. Fish oil supplementation decreased lymphocyte proliferation (21 days: P < 0.0001; 28 days: P < 0.0001) and the ratio of CD3+CD4+/CD3+CD8+ (21 days: P = 0.0479; 28 days: P = 0.0009) after LPS challenge. LPS challenge increased the levels of interleukin-1 (IL-1) (21 days: P < 0.0001; 28 days: P = 0.0030), IL-6 (21 days: P < 0.0001; 28 days: P = 0.0001) and tumor necrosis factor-α (TNF-α) (21 days: P = 0.0008; 28 days: P = 0.0018). And fish oil alleviated the elevations in the production of IL-6 (21 days: P = 0.0359; 28 days: P = 0.0302) and TNF-α (21 days: P = 0.0055; 28 days: P = 0.0391) induced by the LPS challenge. Fish oil alleviated the mRNA abundance elevation of nuclear factor kappa B (NFκB) (21 days: P = 0.0079; 28 days: P = 0.0017) after LPS challenge. These results showed that fish oil acts as an anti-inflammatory agent, which may be associated with down-regulation of the activated immune system. The results of pro-inflammatory cytokines and mRNA abundance results suggested that fish oil might alleviate the elevation of IL-6 and TNF-α induced by LPS through down-regulating NFκB expression.

Lactic acid bacteria have traditionally been thought to have immunomodulating effects. To verify this property, Lactobacillus plantarum was orally administered to mice (5 × 107 colony forming units (c.f.u.)), prior to infection with Listeria monocytogenes in order to evaluate the host resistance against an infectious micro-organism and to better define the influence of L. plantarum on such responses. Balb/c mice were treated daily with L. plantarum or received PBS (sham-treated mice as controls) for 4 weeks. Subsequently, mice were intravenously infected with a clinical isolate of L. monocytogenes. Our study revealed that the administration of L. plantarum did not significantly increase the survival (P = 0·13) of mice (fifteen in each group) after L. monocytogenes infection (106 c.f.u./ml), whereas a sub-lethal dose of L. monocytogenes (105 c.f.u./ml) was eliminated from liver and spleen 5 d after the challenge in both L. plantarum- and sham-treated mice (n 5). Nevertheless, the levels of IL-1β and IL-6 from sera of orally administered L. plantarum were drastically reduced at 0, 4 (P < 0·01) and 6 d after L. monocytogenes infection, whereas TNF-α production was unaltered. In conclusion, administration of L. plantarum reduced pro-inflammatory IL production after challenge with L. monocytogenes, although it did not significantly impact the survival of mice. We speculate that L. plantarum could exert anti-inflammatory effects, which may represent an important model to reduce inflammatory disorders. Therefore, further studies in human subjects should determine the role of L. plantarum as an immunomodulatory micro-organism and its relationship in the host protection to pathogens.

Malaria kills approximately 1–2 million people every year, mostly in sub-Saharan Africa and in Asia. These deaths are at the most severe end of a scale of pathologies affecting approximately 500 million people per year. Much of the pathogenesis of malaria is caused by inappropriate or excessive immune responses mounted by the body to eliminate malaria parasites. In this review, we examine the evidence that immunopathology is responsible for malaria disease in the context of what we have learnt from animal models of malaria. In particular, we look in detail at the processes involved in endothelial cell damage leading to syndromes such as cerebral malaria, as well as generalised systemic manifestations such as anaemia, cachexia and problems with thermoregulation of the body. We also consider malaria in light of the variation of the severity of disease observed among people, and discuss the contribution from animal models to our understanding of this variation. Finally, we discuss some of the implications of immunopathology, and of host and parasite genetic variation, for the design and implementation of anti-malarial vaccines.