Aerobic Fitness Affects Cardiovascular and Catecholamine Responses to Stressors

Subjects of varying degrees of aerobic fitness were subjected to four laboratory stressors in a test of the hypothesis that aerobic fitness is associated with decreased responsiveness to stressors other than exercise. Blood pressure, heart rate, norepinephrine, epinephrine, and psychological responses to a film of industrial accidents (passive psychological stressor), the Stroop word color task (active psychological stressor), the cold pressor test (passive physical stressor), and running to exhaustion on a treadmill (active physical stressor) were measured. Baseline systolic blood pressure and relative diastolic responses to the film, Stroop task, and exercise were smaller in fit subjects over 40 than in less fit subjects of the same age group. Heart rates were lower in fit subjects at most times, except during and after maximal exercise. Norepinephrine was lower after 9 min of exercise in fit subjects, but was much higher at exhaustion, after these subjects had accomplished more work. Norepinephrine levels fell rapidly and were not different among groups 3 and 10 min after exercise. There was no preferential generalization of the “fitness effect” to the active psychological task.     

Differential effects of active and passive laboratory stressors on immune function in healthy men

The immunomodulatory effects of acute laboratory stressors were examined by comparing active and passive stressors in a between-subjecls design. Healthy male volunteers (N = 67) were recruited and randomly assigned to an active. passive, or no stressor condition. Subjects were exposed to either the Stroop and mental arithmetic tasks (active), two surgery films (passive), or two nature films (no stress). Cardiovascular reactivity, plasma catecholamines and Cortisol. and self-reported distress were measured pretask and posttask. Lymphocyte proliferation to concanavalin A (Con A), pokeweed mitogen (PWM), and phytohemagglutinin was assessed at baseline, after the first task, after the second task, and 30 min later. Lymphocyte proliferation to Con A and PWM was significantly reduced in response to the stressors. Different response patterns emerged, depending on the type of stressor and the mitogen used. Changes in lymphocyte proliferation were significantly associated with cardiovascular reactivity during the tasks. Results are discussed in terms of potency of the stressors and mechanisms underlying passive versus active laboratory tasks. Implications for future research are addressed. This study was supported by Uniformed Services University of the Health Sciences Grant R0726S     

The temporal redistribution pattern of NK cells under acute stress based on CD62L adhesion molecule expression

Recent studies demonstrated that an acute psychological stressor elicited transient changes in lymphocyte redistribution. Earlier studies had established that CD3-CD16+CD56+ natural killer cells (NK cells) increased remarkably in peripheral blood circulation and that the amount of lymphocyte redistribution in NK cells was dependent on the CD62L expression density. Specifically, CD62L- cells were mobilized more pronouncedly than were CD62L+ cells. These results led us to hypothesize that such different reactivity causes different temporal characteristics between CD62L+ and CD62L- lymphocyte subsets. The present study was conducted to examine this issue. Ten female participants experienced a 10-minute baseline period and performed a 10-minute mental arithmetic task as an acute psychological stressor. Blood samples for measuring the proportions of CD62L+ or CD62L- NK cells and CD62L+ or CD62L- T cells were obtained immediately after each period and every 2 min during the task. As expected, CD62L+ and CD62L- NK cells showed different reactivity in response to the stressor and showed different temporal characteristics. That is, the elevation of CD62L- NK cells reached a significant level at 1 min after the initiation of the stressor, while CD62L+ NK cells took 8 min to show a tendency of elevation. Although CD3+ T cells showed different reactivity between CD62L cell types, they did not show different temporal characteristics. These findings suggest that the expression of CD62L modulates not only the amount of redistribution but also the temporal characteristics of the redistribution of NK cells.     

Modulatory effects of defense and coping on stress-induced changes in endocrine and immune parameters

We examined whether habitual defense and coping affect the response of hormones (ACTH. cortisol, prolactin. endorphins, and noradrenaline) and immune parameters (numbers of T cells. B cells. natural killer [NK] cells, and proliferative responses to mitogens or antigens) to an acute laboratory stressor (i.e., solving a 3-dimensional puzzle and explaining it to a confederate) in 86 male high school teachers. Defense and coping were assessed by Kragh's tachistoscopic Defense Mechanism Test (a measure of perceptual defense) and by 4 questionnaire-based coping styles assessing instrumental mastery-oriented coping, emotion-focused coping, cognitive defense, and defensive hostility. The laboratory stressor per se caused a relative increase in immunological (in particular NK cells) and endocrine (cortisol, prolactin) parameters. Defense and coping, however, significantly codetermined the response to the stressor. In particular, instrumental mastery-oriented coping and perceptual defense were related to stress-induced changes in numbers of B cells and in the pituitary-adrenal hormones. The results indicate that the impact of a mild psychological stressor on the immune and endocrine system depends to a considerable extent on the specific ways people deal with stressors.     

Children's and adults' salivary alpha‐amylase responses to a laboratory stressor and to verbal recall of the stressor

Salivary alpha‐amylase (sAA), an enzyme produced by the salivary glands, increases in response to physical and psychosocial stressors in adults. Whether similar increases are evident among children, though, is less clear, and there is a lack of studies directly comparing children's and adults' sAA responses to an identical stressor. In this study, 24 children (9–12 years; 12 female) and 26 adults (18–23 years; 16 female) were exposed to an identical psychosocial laboratory stressor and a recall interview regarding that stressor after a 2‐week delay. Saliva was collected before and 1, 10, 20, and 30 min after the stressor/recall interview. Among adults, concentrations of sAA increased on both study days, but similar increases were not detected among children. Findings suggest developmental differences in sAA reactivity, and underscore the need to characterize the confluence of elements that will reliably elicit sAA responses to mild stress in youth. © 2010 Wiley Periodicals, Inc. Dev Psychobiol 52: 598–602, 2010.     

A comparison of acute stress paradigms: hormonal responses and hypothalamic serotonin

The effects of stress on plasma renin activity (PRA), plasma prolactin and corticosterone levels, and hypothalamic 5-HT and 5-HIAA concentrations were investigated using a 3 and 12 min conditioned fear (CER) paradigm; 20 min immobilization; 20 min exposure to shallow or deep cold water; 2, 12 and 22 min of intermittent footshock with or without 20 min recovery; and, a 3 min CER with 0, 10, 30 and 60 min recovery. PRA was increased by all the stressors, except shallow cold water, reaching a maximum after 12 min and returning to control values within 10-20 min post-stress. Prolactin levels also were increased by all the stressors, except shallow and deep cold water. Prolactin levels were maximal after 12 min and returned to baseline within 20-60 min post-stress, depending on the stressor. Corticosterone levels were elevated by all the stressors, but not as rapidly as PRA or prolactin, reaching a maximum after about 20 min and returning to baseline concentrations within 30-60 min post-stress. None of the stressors produced significant changes in hypothalamic 5-HT and 5-HIAA concentrations.     

Gender differences in cardiovascular and natural killer cell reactivity to acute stress following a hassling task

To determine the influence of increased ambient stress load on subsequent cardiovascular and natural killer (NK) cell reactivity to acute stress, 30 men and women were exposed to a 5-min mental arithmetic (MA) stressor. Half the participants experienced a bureaucratic hassle designed to increase ambient stress load prior to the MA task, and the other half experienced the MA task without this pretreatment. Hassle group x gender effects suggested that hassled men had greater heart rate increases to the MA task than did hassled women, and hassled men had greater NK reactivity to the MA task than did any other group.     

Time-Dependent Differential Changes of Immune Function in Rats Exposed to Chronic Intermittent Noise

Noise is a highly relevant environmental and clinical stressor. Compared to most other experimental stressors, noise is a modest activator of neuroendocrine pathways that mimic the situation in human health where neuroendocrine activation by environmental stressors is often absent or difficult to establish. Little is known about the effects of noise exposure on the immune system. In the present work, the effects of a low-intensity chronic intermittent unpredictable noise regimen on various parameters of immune function was studied. Male wistar rats were exposed to a randomized noise protocol (white noise, 85 dB, 2–20 kHz) for 10 h per day, 15 min per h over a total period of 3 weeks. Control animals were exposed to ambient sound only. Immune function was monitored after 24 h, 7 days, and 21 days of noise exposure. Noise induced several significant changes in immune function in a time-dependent differential pattern involving both immunosuppression and immunoenhancement. After 24 h, serum IgM levels were increased and peripheral phagocytic activity was decreased. Splenic lymphocytic proliferation to mitogens was significantly decreased after 7 days, but slightly elevated after 3 weeks. The activity of splenic NK cells was increased significantly after 24 h and 7 days, but suppressed after 3 weeks. These results show that various parameters of immune function are affected differentially over time in a period of chronic mild noise stress, possibly due to sequential activation of different physiological mechanisms.     

Reactivity and vulnerability to stress-associated risk for upper respiratory illness

OBJECTIVE: We tested the hypothesis that the greater a person's laboratory stress-elicited elevation in cortisol, the greater the life stress-related risk for upper respiratory infection (URI). We also tested the prediction that the greater the laboratory stress-elicited rise in natural killer cell (NK) cytotoxicity, the smaller the life stress-related URI risk. Finally, we explored whether sympathetic nervous system (SNS) and enumerative immune reactivities to laboratory stress moderate the relation between life stress and URI. METHODS: At baseline, 115 healthy subjects were administered a negative stressful life events checklist and were tested to assess their SNS (blood pressure, heart rate, and catecholamines), HPA (cortisol), and immune (NK cell cytotoxicity and lymphocyte subsets) reactivities to laboratory speech tasks administered 2 weeks apart. Responses were averaged across the two laboratory assessments to create reactivity scores. After these assessments were completed, participants were followed weekly for 12 consecutive weeks. At each follow-up they completed a measure of perceived stress experienced over the last week. They were also instructed to contact the study coordinator if they had a cold or flu at any time during follow-up. A health care worker verified reported illnesses. RESULTS: In a traditional prospective analysis, high cortisol reactors with high levels of life events had a greater incidence of verified URI than did high reactors with low levels of life events and low reactors irrespective of their life event scores. Using hierarchical linear modeling, CD8(+) number, Natural Killer (NK) cell number, and NK cell cytotoxicity, each interacted with weekly perceived stress levels in predicting concurrent occurrences of self-reported URIs. For these outcomes, low immune reactors were more likely to experience an URI during high stress than low stress weeks. High immune reactors did not exhibit differences in weekly URIs as a function of weekly stress level. The SNS reactivity markers did not moderate the association of stress and URI incidence in either analysis. CONCLUSIONS: Acute HPA and immune responses to laboratory stressors are markers of how vulnerable people are to the increased risk for URI associated with stressors in the natural environment.     

Modulation of attentional inhibition by norepinephrine and cortisol after psychological stress.

Two of the most salient physiological responses to stress are increased norepinephrine (NE) and cortisol (CORT) activities. However, it is unclear how these neurochemical events affect cognition, especially attention. We examined the effects of mild psychological stress on selective attention, as assessed by the negative priming (NP) paradigm. Salivary measures of the stress hormone CORT and alpha-amylase (a correlate of NE) were assayed to probe the relationship between the stress response and attentional inhibition. Healthy subjects (N = 20) engaged in the attention task, which was then followed by 15 min of a stressful video game before a return to the attentional task. Baseline saliva samples were obtained before the experiment began, 1 min after the video-game stressor, and 20 min post-stress. Subjects showed a significant reduction in NP and a decrease in reaction time (RT) after the video game. Moreover, alpha-amylase levels increased significantly after the stressor, indicating the role of NE in the acute stress response. While CORT levels remained unchanged after stress, CORT correlated significantly with both NP scores and RT after the stressor. These results imply that mild psychological stress can significantly alter attentional processes. Given the increase in alpha-amylase and the correlation between attention and CORT after stress, it seems likely that attentional processes are under tight control by brain systems which mediate the fight-or-flight response.     

Role of prolactin in the modulation of NK and lak cell activity after short- or long-term morphine administration in neoplastic patients

In a previous work we demonstrated that chronic in vivo antalgic therapy of cancer patients with morphine reduced the endogenous cytotoxic activity of natural killer (NK) cells, while increasing the development of lymphokine activated killer (LAK) cell cytotoxicity. In order to investigate the mechanisms by which morphine affects NK and LAK cell function further, we evaluated the modulation exerted by short- or long-term morphine administration on either NK/LAK cell cytotoxicities or plasma levels of prolactin (PRL) and other immunomodulating neurohormones. An intravenous morphine injection (10mg) significantly increased the plasma levels of PRL, reduced the cytotoxic activity of NK cells, and increased the development of LAK cell activity 30 min after drug injection in neoplastic patients. The administration of bromocriptine before the injection of morphine prevented both PRL augmentation and the increase in LAK cell activation, although it did not prevent the inhibition of NK cytotoxicity. The chronic oral administration of morphine (90±30mg/day for 1 month) also resulted in higher PRL levels; the NK and LAK cell activities were, respectively, lower than or higher than those found in neoplastic patients untreated with morphine. The plasma levels of thyrotropin (TSH), adrenocorticotropic hormone (ACTH) and cortisol were not significantly modified in either short- or long-term experiments. The absolute number and the percentages of lymphocyte populations, as well as the percentage of IL-2 receptors, were not modified after short-term morphine administration whereas little changes of T lymphocyte populations and NK cell number were observed after oral treatment with morphine. In vitro morphine did not affect the development of LAK cell activity. In conclusion, our findings indicate that morphine reduces NK cytotoxicity and increases the development of LAK cell cytotoxicity after short- and long-term administration. The effect of morphine on LAK cell activation but not on NK cell reduction is related to the modulation of PRL levels determined by the opioid drug.     

Natural killer cell mediated cytotoxicity of tumor cells initiated by neem leaf preparation is associated with CD40-CD40L-mediated endogenous production of interleukin-12

Neem leaf preparation (NLP) was found to activate natural killer (NK) cells (CD56(+)CD3(-)) to enhance their cytotoxic ability to tumor cells and stimulate the release of interleukin-12 (IL-12) from macrophages from healthy individuals and head-and-neck squamous cell carcinoma patients. NLP upregulated cytotoxic (CD16(+) and CD56(dim)) NK cells, and the cytotoxicity of NK-sensitive K562 cells by NLP-stimulated peripheral blood mononuclear cells decreased significantly after IL-12 neutralization. This NK-mediated cytotoxicity was manifest by upregulation of IL-12-dependent intracellular expression of the perforin-granzyme B system. Moreover, NK cytotoxic function was abolished after use of concanamycin A, a perforin inhibitor, but not by brefeldin A, a Fas inhibitor, confirming the participation of the perforin-granzyme B system. In addition NLP upregulated the expression of CD40 in CD14(+) monocytes and CD40L in CD56(+) lymphocytes. Neutralization of CD40 and CD40L in NLP-stimulated peripheral blood mononuclear cells culture resulted in significant downregulation of IL-12 release and cytotoxicity of NK cells, demonstrating the role of a CD40-CD40L interaction in the observed functions. Signals involved in the NLP-induced release of IL-12, and thereby induction of NK cell cytotoxicity, are mediated by activating p38MAPK pathway, but not through the ERK1/2 signaling pathway. Overall the results suggest that NLP effects NK cellular cytotoxicity by CD40-CD40L-mediated endogenous production of IL-12, which critically controls perforin-dependent tumor cell cytotoxicity.     

Intraocular pressure changes: the influence of psychological stress and the Valsalva maneuver

The effects of psychological stress and the Valsalva maneuver on short-term variations of intraocular pressure (IOP) were studied in 49 healthy adults. Psychological stress consisted of mental arithmetic tasks presented in counterbalanced order by computer and by the experimenter. Additionally, a standardized Valsalva maneuver was performed (in counterbalanced order with the psychological stressors). IOP was measured with a Goldmann tonometer before and after performance of each stressor. All three stressors transiently and highly significantly increased IOP, although the Valsalva maneuver produced changes of a greater magnitude (10.2 mmHg) than the psychological stressors (1.3 mmHg). Subjective stress ratings and heart rate increased in response to all stressors. There were no effects of task sequence, eye muscle tension, sex, smoking status (some smokers misreported their smoking status), or regular marijuana use, but regular physical exercise was associated with less IOP increase during psychological stress.     

Place conditioning and neurochemical responses elicited by the aftereffect of acute stressor exposure involving an elevated stand

Acute exposure to an elevated stand has been used as an inescapable mild stressor for rats. The present study examined the effects of this stressor using a place conditioning behavioral test and neurochemical assays of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the medial prefrontal cortex and nucleus accumbens. The behavioral data showed that a conditioned place preference was formed as an aftereffect of the elevated stand stressor. In a separate experiment, neurochemical assay showed an immediate increase of dopamine in the nucleus accumbens after 30 min exposure to the elevated stand stressor. In addition, the DOPAC content in the nucleus accumbens was significantly increased at 30 min after this stressor. No significant change in dopamine or DOPAC levels in the medial prefrontal cortex was detected for up to 60 min after stressor manipulation. These results suggest that an increase in dopamine activity in the nucleus accumbens is involved in the development of conditioned place preference elicited by the aftereffects of the elevated stand stressor.     

Heightened Psychobiological Reactivity to Laboratory Stressors in Healthy Women at Familial Risk for Breast Cancer

This study examined the possibility that reactivity to acute stressors may be altered among women facing the chronic stress of being at familial risk for breast cancer. Sixteen healthy women with histories of breast cancer in their families (Risk Group) and 32 women at normal risk (Comparison Group) were exposed to 15 min of classic laboratory stressors. Seventeen women at normal risk were randomly assigned to nonstressful tasks (manipulation check). Self-reported distress, natural killer cell activity (NKCA), and NK cell numbers (percentage of CD3-CD16/56+ lymphocytes) were assessed before and after the tasks. Cardiovascular activity was assessed throughout the session. The tasks elicited increases in distress, heart rate, NKCA, and NK cells numbers in both experimental groups. Supporting study hypotheses, the Risk Group had larger increases in distress, heart rate, NKCA, and NK cell numbers. These findings raise the possibility that the chronic stress associated with familial cancer risk may have negative health consequences through changes in psychobiological reactivity.     

Effects of experimental psychological stress on distribution and function of peripheral blood cells.

Fifty male subjects (aged 24 to 55 years) were subjected to a mild and potentially uncontrollable interpersonal stress situation. They were asked to solve a difficult puzzle. Subsequently they were requested to explain their solution to "another subject," actually a confederate to the researchers. The confederate frustrated the subjects' explanation efforts. Care was taken that neither solving nor explaining of the puzzle was successful. The experimental situation induced mild psychological strain as documented by mood changes in the experimental group when compared with a control group of 36 male subjects. Peripheral blood was drawn by an indwelling catheter just before, directly after, 15 minutes after, and 30 minutes after the stress situation. Numbers of leukocytes, lymphocytes, monocytes, T-cell subsets, natural killer (NK) cells, and B-cells were determined. As functional assays we used in vitro proliferative responses of T- and B-cells to mitogenic stimulation (PHA and PWM) and to an antigen cocktail. The potential influences of health- and biobehavioral variables were taken into account in the analyses, as well as incidental differences in initial mood or immunological baseline. The results replicated and expanded on previous research. In contrast to controls, experimental subjects showed a significant increase in numbers of NK cells after the stress-period, returning to baseline values after 15 minutes of rest. A similar effect was shown on T-suppressor/cytotoxic cells and, inversely, on T-helper/suppressor ratio, but these effects could be attributed to changes in the numbers of CD8+CD57+ cells. No effects were observed on proliferation. From the results we conclude that the effects of a short lasting mild psychological stressor are mainly restricted to cells of the NK cell population.     

Immunological changes in young and old adults during brief laboratory stress

Few data are available on the response of the human immune system to acute psychological stressors under controlled laboratory conditions. Young female subjects (21-41 years) showed increases in natural killer (NK) cell activity, and in the numbers of circulating CD8 suppressor/cytotoxic T cells, and natural killer lymphocytes following a brief (12 minute) stressful mental arithmetic examination. Older female subjects (65-85 years) failed to show the stress-related increase in NK activity. The psychological stress did lead to increases in the numbers of circulating CD8 suppressor/cytotoxic T cells and NK lymphocytes in old subjects to a similar degree as that seen in the young group. No changes in the numbers of helper/inducer T cells (CD4), total T cells (CD3), or B cells (CD20) were found following the stressor for either group. Cardiovascular, catecholamine, and subjective stress responses were similar for the two age groups. These results demonstrate that brief psychological stress is associated with some rapid immune cell changes, including release of CD8 suppressor/cytotoxic T cells and NK cells into circulation, and in young subjects, increases in NK activity. The absence of an NK activity increase in the older subjects indicates that NK cell mobilization and cell lysis induced by NK cells may be differentially affected by stress. The results also suggest the possibility of an age-related deficit in the up-regulation of NK activity under some environmental demands.     

Catecholamines induce alterations of distribution and activity of human natural killer (NK) cells

Catecholamines have been suggested to be responsible for altered cellular immunity after stress. This study was performed to determine the effects of adrenaline and noradrenaline on lymphocyte subpopulations and NK cell functions. Subjects were given a subcutaneous injection of either NaCl, adrenaline (5 µg/kg), or noradrenaline (10 µg/kg). Catecholamine concentrations, subsets of peripheral blood lymphocytes, NK activity, and antibody-dependent cellular cytotoxicity (ADCC) were analyzed before (baseline) and 5, 15, 30, 60, and 120 min after injection. There were no differences between groups in the distribution of CD2⁺ and CD8⁺ lymphocytes over time. However, CD3⁺ and CD4⁺ T cells decreased significantly 5 to 60 min after injection of adrenaline. In contrast, NK cell numbers (CD16⁺, CD56⁺) increased significantly 5 min after injection of adrenaline and noradrenaline, reached the highest values 15 to 30 min postinjection, and subsequently declined to baseline values 60 (noradrenaline) and 120 (adrenaline) min, respectively, after injection. Similar alterations for NK activity and ADCC were observed after administration of both catecholamines. These data suggest that both sympatheticadrenal hormones are similarly potent modulators of natural immunity and provide further evidence that catecholamines might be responsible for the observed alterations in immune functions after phases of acute stress.     

NKp30 受体在肿瘤和感染性疾病中的研究进展

NK 细胞是机体抗感染和抗肿瘤的第一道天然防线,其活性主要受其表面的活化性和抑制性两类受体调控。NKp30 作为NK 细胞活化性受体,通过与其相应配体结合在对肿瘤和病原体感染细胞的免疫监视及杀伤中发挥着重要的作用。而在一些患者血清中发现高浓度的可溶性配体,这些配体可与NKp30 结合,降低NKp30 介导的NK 细胞杀伤活性。另外,在组织中主要表达NKp30a、b、c 三种剪切异构体,三种异构体的表达谱对多种疾病的预后具有潜在的评估价值,并且与疾病的临床症状相关。因此,NKp30 可能成为肿瘤和感染性疾病免疫治疗的新靶点及疾病早期评价的新指标。     

Modulation of human natural killer cytotoxicity by influenza virus and its subunit protein.

The influence of intact influenza virus and purified detergent solubilized haemagglutinin (HA) subunits from these viruses on human natural killer (NK) cell activity was examined. Effector cells incubated with whole influenza virus for 18 hr initiated the production of alpha interferon which was associated with the enhancement of NK cell activity. In contrast, purified influenza virus HA suppressed NK activity in a dose-dependent manner, when added at the onset of the cytotoxicity assay, or when used to pre-treated effector cells prior to assay for cytotoxicity against K562 target cells. Effector cells exposed to influenza HA for 90 min, washed and re-incubated in fresh medium for up to 18 hr, failed to regain their cytotoxicity. Suppression of NK cell cytotoxicity could not be ascribed to direct toxicity of HA preparations or residual detergent and preservative in these preparations. The augmented cytotoxicity of activated human effector cells was also susceptible to suppression by virus HA, and pretreatment of human PBL effector cells with HA for 90 min, prior to exposure to human alpha interferon caused NK effector cells to become refractive to the enhancing effects of HIFN. That direct interaction between influenza virus HA and effector cells was a requirement for suppression of activity was shown in experiments using Bromelain-released influenza HA, which would not be expected to bind to cells and which failed to suppress NK cell activity.