Stress-induced Immune Suppression Research Articles

Dietary Aspergillus oryzae Modulates Serum Biochemical Indices, Immune Responses, Oxidative Stress, and Transcription of HSP70 and Cytokine Genes in Nile Tilapia Exposed to Salinity Stress.

Simple SummaryProbiotics are live microbial adjuncts with numerous beneficial effects on fish. This study aims to evaluate the roles of Aspergillus oryzae (ASP) in the modulation of serum haemato-biochemical measurements, immunity, antioxidative capacity, and transcriptomic responses of Nile tilapia juveniles exposed to salinity stress. Findings revealed that dietary supplementation with A. oryzae mitigated the harmful influences of salinity stress on the exposed Nile tilapia.Nile tilapia Juveniles (19.50 ± 0.5 g) were fed on a basal diet (control group (CTR)) and a diet supplemented with 1 g Aspergillus oryzae (ASP) per kg diet for 12 weeks. Fish were then subjected to different salinity levels (0, 10, 15, and 20 practical salinity units (psu)) for another 15 days. Two-way ANOVA analysis revealed that the individual effects of ASP in Nile tilapia exposed to salinity levels presented a significant decrease (p < 0.05) in values of haemato-biochemical indices (such as glucose, cortisol, alanine transaminase, aspartate transaminase, and malondialdehyde) compared to those in the CTR group exposed to the same salinity levels. Moreover, significant increases (p < 0.05) of blood protein profile (albumin, globulin, and total protein), non-specific immune responses (lysozyme activity, phagocytic activity, and phagocytic index), and antioxidant enzymes activities (glutathione peroxidase, catalase, and superoxide dismutase) were observed in ASP-supplemented groups. Interestingly, there was significant (p < 0.05) downregulation of the mRNA expression values of heat shock protein 70 and interferon-gamma genes, alongside upregulation of the mRNA expression values of interleukin 1 beta and interleukin 8 genes, in the hepatic tissues of Nile tilapia in ASP-supplemented groups exposed to different salinities compared to those in the CTR group exposed to the same salinity levels. Taken together, these findings supported the potential efficacy of dietary supplementation with ASP in alleviating salinity stress-induced haemato-biochemical alterations, immune suppression, and oxidative stress in the exposed Nile tilapia.

Hypoxic Stress-Induced Tumor and Immune Plasticity, Suppression, and Impact on Tumor Heterogeneity

The microenvironment of a developing tumor is composed of proliferating cancer cells, blood vessels, stromal cells, infiltrating inflammatory cells, and a variety of associated tissue cells. The crosstalk between stromal cells and malignant cells within this environment crucially determines the fate of tumor progression, its hostility, and heterogeneity. It is widely accepted that hypoxic stresses occur in most solid tumors. Moreover, cancer cells found within hypoxic regions are presumed to represent the most aggressive and therapy-resistant fractions of the tumor. Here, we review evidence that hypoxia regulates cell plasticity, resistance to cell-mediated cytotoxicity, and immune suppression. Exposure to hypoxia occurs as a consequence of insufficient blood supply. Hypoxic cells activate a number of adaptive responses coordinated by various cellular pathways. Accumulating data also suggest that hypoxic stress in the tumor microenvironment promotes tumor escape mechanisms through the emergence of immune-resistant tumor variants and immune suppression. Thus, solid tumors seem to build up a hostile hypoxic microenvironment that hampers cell-mediated immunity and dampen the efficacy of the immune response.

TGF-β1/Smad2/3/Foxp3 signaling is required for chronic stress-induced immune suppression

Depending on the duration and severity, psychological tension and physical stress can enhance or suppress the immune system in both humans and animals. Although it has been established that chronic stress exerts a significant suppressive effect on immune function, the mechanisms by which affects immune responses remain elusive. By employing an in vivo murine system, we revealed that TGF-β1/Smad2/3/Foxp3 axis was remarkably activated following chronic stress. Furthermore, TLR9 and p38 MAPK played a critical role in the activation of TGF-β1/Smad2/3/Foxp3 signaling cascade. Moreover, inhibition of TGF-β1/Smad2/3/Foxp3 or p38 significantly attenuated chronic stress-induced lymphocyte apoptosis and apoptosis-related proteins, as well as the differentiation of T regulatory cells in spleen. Interestingly, disequilibrium of pro-inflammatory and anti-inflammatory cytokines balance caused by chronic stress was also rescued by blocking TGF-β1/Smad2/3/Foxp3 axis. These findings yield insight into a novel mechanism by which chronic stress modulates immune functions and identifies new targets for the development of novel anti-immune suppressant medications.

Anti-stress effect of the Lactobacillus pentosus strain S-PT84 in mice.

We investigated if the orally administered Lactobacillus pentosus strain S-PT84 (S-PT84) might show anti-stress activity and ameliorate stress-induced immune suppression in mice. Stress of mice induced an increase in serum corticosterone and a decrease in splenic natural killer activity and in the number of splenocytes versus control mice. However, these changes were not observed in stressed mice that had been administered S-PT84. Furthermore, interleukin (IL)-12 and IL-10 production, which was downregulated in lipopolysaccharide-activated macrophages from stressed mice, was maintained at control levels in the macrophages of stressed mice that had been fed S-PT84. Interferon-γ production, which was downregulated in concanavalin A-activated splenocytes from stressed mice, tended to be maintained at control levels in stressed mice that had been fed S-PT84, although IL-4 production by these cells was not influenced by S-PT84 administration. Additionally, reduced glutathione (GSH) levels were decreased in serum and peritoneal macrophages from stressed mice versus controls, but these GSH levels were significantly higher in stressed animals that had been administered S-PT84 compared with those that had not. These results suggest that S-PT84 exerts anti-stress activity through immune modulation and/or antioxidative activity.

Interaction Between 2 Nutraceutical Treatments and Host Immune Status in the Pediatric Critical Illness Stress-Induced Immune Suppression Comparative Effectiveness Trial.

The pediatric Critical Illness Stress-induced Immune Suppression (CRISIS) trial compared the effectiveness of 2 nutraceutical supplementation strategies and found no difference in the development of nosocomial infection and sepsis in the overall population. We performed an exploratory post hoc analysis of interaction between nutraceutical treatments and host immune status related to the development of nosocomial infection/sepsis. Children from the CRISIS trial were analyzed according to 3 admission immune status categories marked by decreasing immune competence: immune competent without lymphopenia, immune competent with lymphopenia, and previously immunocompromised. The comparative effectiveness of the 2 treatments was analyzed for interaction with immune status category. There were 134 immune-competent children without lymphopenia, 79 previously immune-competent children with lymphopenia, and 27 immunocompromised children who received 1 of the 2 treatments. A significant interaction was found between treatment arms and immune status on the time to development of nosocomial infection and sepsis ( P < .05) and on the rate of nosocomial infection and sepsis per 100 patient days ( P < .05). Whey protein treatment protected immune-competent patients without lymphopenia from infection and sepsis, both nutraceutical strategies were equivalent in immune-competent patients with lymphopenia, and zinc, selenium, glutamine, and metoclopramide treatment protected immunocompromised patients from infection and sepsis. The science of immune nutrition is more complex than previously thought. Future trial design should consider immune status at the time of trial entry because differential effects of nutraceuticals may be related to this patient characteristic.

Diagnosis and Treatment of Ventilator-Associated Infection: Review of the Critical Illness Stress-Induced Immune Suppression Prevention Trial Data.

The Critical Illness Stress-Induced Immune Suppression prevention trial was a randomized, masked trial of zinc, selenium, glutamine, and metoclopramide compared with whey protein in delaying nosocomial infection in PICU patients. One fourth of study subjects were diagnosed with nosocomial lower respiratory infection, which contributed to subjects receiving antibiotics 74% of all patient days in the PICU. We analyzed diagnostic and treatment variability among the participating institutions and compared outcomes between nosocomial lower respiratory infection subjects (n = 74) and intubated subjects without nosocomial infection (n = 1 55). Post hoc analysis. Eight hospitals in the Collaborative Pediatric Critical Care Research Network. Critical Illness Stress-Induced Immune Suppression study subjects. None. Variability across institutions existed in the frequency and manner by which respiratory secretion cultures were obtained, processed, and results reported. Most results were reported semiquantitatively, and both Gram stains and antibiotic sensitivities were frequently omitted. The nosocomial lower respiratory infection diagnosis was associated with increased PICU lengths of stay compared with those who were intubated without nosocomial infection (24 ± 19 vs 9 ± 6 d; p < 0.001) and antibiotic use (38 ± 29 vs 15 ± 20 antibiotics days; p < 0.001). Despite antibiotic treatment, the same bacteria persisted in 45% of follow-up cultures. The Critical Illness Stress-Induced Immune Suppression data demonstrate that the nosocomial lower respiratory infection diagnosis is associated with longer lengths of stay and increased antibiotic use, but there is considerable diagnostic and treatment variability across institutions. More rigorous standards for when and how respiratory cultures are obtained, processed, and reported are necessary. Bacterial persistence also complicates the interpretation of follow-up cultures.

Diagnosis and Treatment of Ventilator-Associated Infection: Review of the Critical Illness Stress-Induced Immune Suppression Prevention Trial Data

目的 危重症应激性免疫抑制(critical illness stress-induced immune suppression，CRISIS)预防试验为一项比较联合补充锌、硒、谷氨酰胺及胃复安与单独补充乳清蛋白对推迟PICU患儿院内感染发生有无差异的随机盲法研究。研究对象中1/4存在院内下呼吸道感染(lower respiratory infection，LRI)，并造成患儿74% PICU总住院日接受抗生素治疗。本研究分析各参与医疗机构间院内LRI诊断及治疗差异，并比较院内LRI患儿(n＝74)与无院内感染插管患儿之间的预后差异(n＝155)。 设计 析因分析。 场所 儿童危重症研究合作网内的8家医院。 对象 CRISIS研究对象。 干预措施 无。 测量方法和主要结果 各医疗机构采集，处理呼吸道分泌物，及报告培养结果的频率及方式存在差异。多数结果以半定量形式报告，且常省略革兰染色及抗生素敏感性结果。对比气管插管但无院内感染患儿，院内LRI与PICU住院时间(24±19 vs.9±6 d，P<0.001)及抗生素使用时间(38±29 vs.15±20 d，P<0.001)延长有关，尽管予抗生素治疗，45%后续培养所得细菌与前相同。 结论 CRISIS研究显示院内LRI与住院时间延长及抗生素使用增加有关，但各医疗机构在诊断及治疗方面差异较大。须针对呼吸道培养标本采集，处理及结果报告制定更为严格的标准。细菌持续存在也会增加后续培养结果的解读难度。

Essential role of IL-10/STAT3 in chronic stress-induced immune suppression

Stress can either enhance or suppress immune functions depending on a variety of factors such as duration of stressful condition. Chronic stress has been demonstrated to exert a significant suppressive effect on immune function. However, the mechanisms responsible for this phenomenon remain to be elucidated. Here, male C57BL/6 mice were placed in a 50-ml conical centrifuge tube with multiple punctures to establish a chronic restraint stress model. Serum IL-10 levels, IL-10 production by the splenocytes, and activation of STAT3 in the mouse spleen were assessed. We demonstrate that IL-10/STAT3 axis was remarkably activated following chronic stress. Moreover, TLR4 and p38 MAPK play a pivotal role in the activation of IL-10/STAT3 signaling cascade. Interestingly, blocking antibody against IL-10 receptor and inhibition of STAT3 by STAT3 inhibitor S3I-201 attenuates stress-induced lymphocyte apoptosis. Inhibition of IL-10/STAT3 dramatically inhibits stress-induced reduction in IL-12 production. Furthermore, disequilibrium of Th1/Th2 cytokine balance caused by chronic stress was also rescued by blocking IL-10/STAT3 axis. These results yield insight into a new mechanism by which chronic stress regulates immune functions. IL-10/STAT3 pathway provides a novel relevant target for the manipulation of chronic stress-induced immune suppression.

Stimulatory Toll-like receptor 2 suppresses restraint stress-induced immune suppression

Stress can enhance or suppress immune functions depending on a variety of factors. Our previous studies observed that Toll-like receptor 2 (TLR2) participates in chronic restraint stress-induced immune dysfunction. However, the mechanism by which TLR2 prevents immune suppression remains elusive. Our investigation found that stimulation of TLR2 by peptidoglycan (PGN) significantly attenuates splenocyte apoptosis and markedly blocks alterations of anti-apoptotic and apoptotic proteins. Activation of TLR2 inhibits chronic stress-reduced phosphorylation of c-Jun N-terminal kinase (JNK) and diminishes chronic stress-induced up-regulation of corticosterone production. Additionally, our data show that chronic stress causes a dramatic decrease of cytokine IL-2 level but an increase of IL-4 and IL-17 in CD4+ T cells. Interestingly, PGN could block these alterations of cytokine levels. Collectively, our studies demonstrate that stimulation of TLR2 attenuates chronic stress-induced immune suppression by modulating apoptosis-related proteins and immunoregulatory agents.

The Role of the Data and Safety Monitoring Board in a Clinical Trial

Randomized clinical trials are commonly overseen by a Data and Safety Monitoring Board comprised of experts in medicine, ethics, and biostatistics. Data and Safety Monitoring Board responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. Data and Safety Monitoring Board decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate Data and Safety Monitoring Board oversight into the design, monitoring, and reporting of randomized trials. Case study, narrative review. The Data and Safety Monitoring Board's role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described. The National Institutes of Health-appointed CRISIS Data and Safety Monitoring Board was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested Data and Safety Monitoring Board interim review before opening CRISIS to children below 1 yr of age. The first interim analysis found higher 28-day mortality in one treatment arm. The Data and Safety Monitoring Board maintained trial closure to younger children and requested a second interim data review 6 months later. At this second meeting, mortality was no longer of concern, whereas a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the Data and Safety Monitoring Board elected to examine conditional power and unmask treatment arm identities. On finding somewhat greater efficacy in the placebo arm, the Data and Safety Monitoring Board recommended stopping CRISIS due to futility. The design and operating procedures of a multicenter randomized trial must consider a pivotal Data and Safety Monitoring Board role. Maximum study design flexibility must be allowed, and investigators must be prepared for protocol modifications due to interim findings. The Data and Safety Monitoring Board must have sufficient clinical and statistical expertise to assess potential importance of interim treatment differences in the setting of multiple looks at accumulating data with numerous outcomes and subgroups.

A critical role of Toll-like receptor 2 in chronic stress-induced immune suppression (P6309)

Abstract Stress can enhance or suppress immune functions depending on the duration and severity of stressful situation. Our previous studies observed that Toll-like receptor (TLR) participates in chronic restraint stress-induced immune dysfunction. However, the mechanism by which TLR2 contributes to immune suppression induced by chronic restraint stress remains elusive. Our investigation found that stimulation of TLR2 by peptidoglycan (PGN), a TLR2 ligand, significantly attenuates cell apoptosis in splenocytes induced by chronic restraint stress. Furthermore, we found that administration of PGN markedly blocks chronic restraint stress-induced alterations of anti-apoptotic and apoptotic genes, including Bcl/2 and glycogen synthase kinase-3β (GSK-3β). We also found that activation of TLR2 by PGN inhibits chronic stress-reduced level of c-Jun N-terminal kinase (JNK) phosphorylation. This effect of PGN is abolished in TLR2 deficient mice, suggesting PGN-induced protection of JNK phosphorylation through a TLR2 dependent manner. Moreover, our data have shown that chronic stress caused a dramatic decrease in cytokine IL-2 level but an increase in the cytokines IL-4 and IL-17 in CD4+ T cells. Interestingly, stimulation of TLR2 by PGN could block these alterations of cytokine levels induced by chronic stress. Collectively, our studies thus demonstrate that stimulation of TLR2 attenuates chronic stress-induced immune suppression by modulating apoptosis-related proteins and cytokines.

The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial*

Nosocomial infection/sepsis occurs in up to 40% of children requiring long-term intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and/or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein, would reduce the occurrence of nosocomial infection/sepsis in this at-risk population. Randomized, double-blinded, comparative effectiveness trial. Eight pediatric intensive care units in the National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Two hundred ninety-three long-term intensive care patients (age 1-17 yrs) expected to require >72 hrs of invasive care. Patients were stratified according to immunocompromised status and center and then were randomly assigned to receive daily enteral zinc, selenium, glutamine, and intravenous metoclopramide (n = 149), or daily enteral whey protein (n = 144) and intravenous saline for up to 28 days of intensive care unit stay. The primary end point was time to development of nosocomial sepsis/infection. The analysis was intention to treat. There were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection/sepsis (median whey protein 13.2 days vs. zinc, selenium, glutamine, and intravenous metoclopramide 12.1 days; p = .29 by log-rank test) or the rate of nosocomial infection/sepsis (4.83/100 days whey protein vs. 4.99/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection/sepsis with zinc, selenium, glutamine, and intravenous metoclopramide in this immunocompromised group (6.09/100 days whey protein vs. 1.57/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .011). Compared with whey protein supplementation, zinc, selenium, glutamine, and intravenous metoclopramide conferred no advantage in the immune-competent population. Further evaluation of zinc, selenium, glutamine, and intravenous metoclopramide supplementation is warranted in the immunocompromised long-term pediatric intensive care unit patient.

β-Arrestin 2-Mediated Immune Suppression Induced by Chronic Stress

Objective: Stress, either physical or psychological, can modulate immune function. However, the mechanisms associated with stress-induced immune suppression remain to be elucidated. β-Arrestin 2 serves as adaptor, scaffold, and/or signal transducer. The role of β-arrestin 2 in stress-induced immune suppression is not known yet. Methods/Results: Here, we demonstrate that β-arrestin 2 deficiency in mice increases the sensitivity to the chronic stress-induced reduction in the number of splenocytes. Interestingly, the stress-induced suppression of T helper-type (Th) 1 cytokines and the increased production of Th2 cytokines were greatly enhanced in β-arrestin 2-deficient mice compared with wild-type mice. Moreover, inhibition of PI3K in β-arrestin 2-deficient mice exerts an additive effect on the stress-induced reduction in the number of splenocytes. Conclusion: Our study demonstrates that a deficiency in β-arrestin 2 augments stress-induced immune suppression.

Use of Nutrition to Prevent Stress‐induced Immunosuppression in the Pediatric Intensive Care Unit: A Clinical Trials Minefield

utrition measures intended to prevent stressinduced, immunosuppression-related morbidity in critically ill patients are receiving increased attention. Supplements such as glutamine, arginine, ω-3 fatty acids, antioxidants, zinc, and others have become candidates for such prophylaxis. Infections, especially sepsis, which occur all too commonly, are targets of these interventions. The mechanistic foundations on which these interventions are based are largely derived from studies of highly stressed animals and from cell cultures. These studies have provided a strong rationale for several treatments, especially glutamine supplementation. Furthermore, several single-center studies as well as meta-analyses of these studies in critically ill adults reveal a significant benefit of glutamine supplementation on mortality, length of stay, and infectious morbidity. Glutamine supplementation has become standard of care in certain populations. Randomized, multicenter clinical trials using glutamine as both nutrition replacement and pharmacologic intervention, independent of nutrition needs, are ongoing in adults. In this issue of the Journal of Parenteral and Enteral Nutrition (JPEN), Carcillo and colleagues 1 propose a multicenter randomized trial of glutamine, zinc, selenium, and parenteral metoclopramide, titled prevention of Critical Illness Stress-induced Immune Suppression (CRISIS) in the pediatric intensive care unit (PICU), and present the plan for this trial. The trial is designed to determine whether this intervention prolongs the time until onset of nosocomial infection or sepsis and secondarily decreases the rate of nosocomial infection or clinical sepsis per 100 PICU days; the trial also will determine the number of antibiotic-free days, the incidence of prolonged lymphopenia, and all-cause 28-day mortality.

Rationale and Design of the Pediatric Critical Illness Stress‐Induced Immune Suppression (CRISIS) Prevention Trial

Despite implementation of CDC recommendations and bundled interventions for preventing catheter-associated blood stream infection, ventilator-associated pneumonia, or urinary catheter-associated infections, nosocomial infections and sepsis remain a significant cause of morbidity and mortality in critically ill children. Recent studies suggest that acquired critical illness stress-induced immune suppression (CRISIS) plays a role in the development of nosocomial infection and sepsis. This condition can be related to inadequate zinc, selenium, and glutamine levels, as well as hypoprolactinemia, leading to stress-induced lymphopenia, a predominant T(H)2 monocyte/macrophage state, and subsequent immune suppression. Prolonged immune dysfunction increases the likelihood of nosocomial infections associated with invasive devices. Although strategies to prevent common complications of critical illness are routinely employed (eg, prophylaxis for gastrointestinal bleeding, thrombophlebitis), no prophylactic strategy is used to prevent stress-induced immune suppression. This is the authors' rationale for the pediatric CRISIS prevention trial (NCT00395161), designed as a randomized, double-blind, controlled clinical investigation to determine if daily enteral supplementation with zinc, selenium, and glutamine as well as parenteral metoclopramide (a dopamine 2 receptor antagonist that reverses hypoprolactinemia) prolongs the time until onset of nosocomial infection or sepsis in critically ill children compared to enteral supplementation with whey protein. If effective, this combined nutritional and pharmacologic approach may lessen the excess morbidity and mortality as well as resource utilization associated with nosocomial infections and sepsis in this population. The authors present the design and analytic plan for the CRISIS prevention trial.

Chronic restraint stress promotes immune suppression through Toll-like receptor 4-mediated phosphoinositide 3-kinase signaling

Stress, either psychological or physical, can have a dramatic impact on the immune system. Toll-like receptors (TLRs) play a pivotal role in the induction of innate and adaptive immune response. We have reported that stress modulates the immune response in a TLR4-dependent manner. However, the mechanisms underlying TLR4-mediated signaling in stress modulation of immune system have not been identified. Here, we demonstrate an essential role for the TLR4-mediated phosphoinositide 3-kinase (PI3K)/Akt signaling. PI3K inhibition by inhibitors wortmannin or LY294002 abrogated protection of stress-induced immune suppression in TLR4-deficient mice compared with TLR4-deficient mice that did not receive the inhibitors. The mechanisms by which PI3K are increased in the TLR4-deficient lymphocytes may involve increased phosphorylation of Akt as well as increased phosphorylation of glycogen synthase kinase-3β (GSK-3β). The stress-mediated suppression of T help 1 (Th1) cytokine and increased production of Th2 cytokine was greatly reduced in TLR4 deficient mice compared with the wild type mice. Moreover, inhibition of PI3K diminished protection of the above Th1 and Th2 changes caused by stress in TLR4-deficient mice compared with non-stressed mice and the wild type mice. Our data demonstrated that TLR4 negatively regulates PI3K activity in wild type mice, leading to the observed the stress-induced immune response. The higher levels of PI3K prevent TLR4 deficient mice from the stress-induced immune response. Therefore, stress modulates the immune system through TLR4-mediated PI3K/Akt signaling.

Toll-like receptor 4 mediates chronic restraint stress-induced immune suppression

Stress, either physical or psychological, can have a dramatic impact on the immune system. Little progress, however, has been made in understanding stress-induced immune suppression. We report here that mice subjected to chronic 12-hour daily physical restraint for two days significantly increased the expression of Toll-like receptor 4 (TLR4). Interestingly, TLR4-deficient mice are resistant to stress-induced lymphocyte reduction. In addition, restraint stress caused dramatic decrease in T help 1 (Th1) cytokine IFN-γ and IL-2 levels but increase in Th2 cytokine IL-4 in wild type mice. Moreover, the restraint stress significantly inhibits changes of Th1 and Th2 cytokines in TLR4-deficient mice compared with the wild type mice. Therefore, stress modulates the immune system through a TLR4-dependent mechanism.

Delayed type hypersensitivity reaction as indicator of cellular immune competence in broiler chickens exposed to dietary corticosterone

Three experiments were performed to evaluate the delayed type hypersensitivity test against keyhole limpet haemocyanin as a parameter to measure stress-induced cellular immune suppression. The test was optimised for broiler chickens and evaluated in a stress model in which plasma corticosterone levels were increased by the administration of 0.5 or 2 mg corticosterone/chicken/day. Keyhole limpet haemocyanin evoked a hypersensitivity type IV response, which was sensitive to increased plasma corticosterone levels. However, the inhibitory effect of 0.5 mg corticosterone/chicken/day was not significantly different from the solvent control (ethanol), because of an inhibitory effect of ethanol itself. The inhibitory effect of 2 mg corticosterone/chicken/day was mainly due to an effect on female chickens, indicating a difference in corticosterone sensitivity between gender. Our data indicate that the delayed type hypersensitivity test against keyhole limpet haemocyanin was sensitive for increased plasma corticosterone concentrations. Therefore this may be an easy and useful test for measuring cell-mediated immunity in corticosterone related immune-suppressed broiler chickens.

Voluntary freewheel running selectively modulates catecholamine content in peripheral tissue and c-fos expression in the central sympathetic circuit following exposure to uncontrollable stress in rats

Modulation of sympathetic drive to the spleen is one potential mechanism whereby physical activity prevents stress-induced splenic immune suppression in rats. The current study tested the hypothesis that voluntary freewheel running reduces peripheral sympathetic drive by modulating stress-induced activity of brain regions synaptically linked to sympathetically innervated peripheral organs, including the adrenals and spleen. To this end, adrenal and splenic catecholamine content and activity of the central sympathetic circuit indexed by c-Fos protein induction, elicited by acute exposure to inescapable tail shock, were measured. Stressor exposure depleted adrenal and splenic norepinephrine content and elicited a robust increase in c-Fos in the brains of sedentary rats. Physical activity status had no effect on adrenal norepinephrine content. Indicative of attenuated sympathetic drive to the spleen, however, 6 weeks of voluntary freewheel running diminished stress-induced splenic norepinephrine depletion, and significantly attenuated stress-induced c-Fos in specific brain regions responsible for sympathetic regulation, including tyrosine hydroxylase-immunoreactive neurons of the locus coeruleus, A5 cell group and rostral ventrolateral medulla. Results suggest that voluntary activity attenuates sympathetic drive to the spleen during stressor exposure by selectively modulating stress-induced activity of the central sympathetic circuit. The attenuation of sympathetic responses observed in this study may be one important mechanism for the protective effect of physical activity against stress-related illness and immunosuppression.

Acute and Chronic Social Defeat Suppresses Humoral Immunity of Male Syrian Hamsters (Mesocricetus auratus)

Stressors, both physical and psychological, can activate the hypothalamic–pituitary–adrenal (HPA) axis, leading to a wide range of physiological responses including increased glucocorticoid release and suppression of immune function. The majority of studies published to date have focused on the effects of physical stressors (e.g., cold exposure, electric shock) on immunity. The present study examined the role of a stressor, social defeat, on humoral immune function of Syrian hamsters (Mesocricetus auratus). Specifically, adult male Syrian hamsters experienced social defeat (i.e., exposure to a dominant animal in that animal's home cage) that was either acute (i.e., a single exposure) or chronic (i.e., daily exposures across 5 days). A control group of animals was placed in a resident's home cage without the resident animal present and did not experience defeat. After the last encounter, blood samples were drawn and animals were subsequently injected with keyhole limpet hemocyanin (KLH). Blood samples were again taken 5 and 10 days postimmunization and serum was analyzed to determine serum cortisol and anti-KLH immunoglobulin G (IgG) concentrations. Cortisol concentrations were elevated in both acutely and chronically defeated hamsters compared with control animals. In contrast, serum IgG concentrations were significantly reduced in both groups of defeated hamsters compared with control animals. Collectively, these results demonstrate that both acute social defeat and chronic social defeat lead to activation of the HPA axis and suppression of humoral immune function. These data suggest that social defeat is an important, ecologically relevant model with which to examine stress-induced immune suppression in rodents.