Chemical sympathectomy increases numbers of inflammatory cells in the peritoneum early in murine listeriosis.

Here, we investigated the effects of sympathectomy on systemic bacterial loads following infection with Listeria monocytogenes, and on innate and specific immune responses in the peritoneum. Sympathectomy decreased systemic bacterial loads, and increased the number of peritoneal leukocytes and the percentage of peritoneal macrophages three days postinfection. This suggests that sympathectomy-induced decreases systemic bacterial loads are associated with increased recruitment of inflammatory cells into tissues during the innate immune response.

Chemical sympathectomy alters numbers of splenic and peritoneal leukocytes.

Sympathectomy of BALB/c mice that were injected with either Listeria monocytogenes or saline did not affect the total number of splenic leukocytes measured 1-3 days after injection, but sympathectomy did increase the percentages of neutrophils in the spleens of both infected and uninfected mice. By contrast, sympathectomy was associated with increased numbers of peritoneal exudate cells (PEC) and peritoneal macrophages in both groups of mice. Sympathectomy did not affect tumor necrosis factor-alpha, interleukin-12, or interferon-gamma production in cultured splenocytes or PEC in either infected or uninfected mice.

Moderate exercise is associated with enhanced antigen-specific cytokine, but not IgM antibody production in aged mice.

It has been suggested that moderate exercise may modulate the immune response in the elderly. We investigated whether moderate exercise had an effect on the immune response to viral infection in both young (2-4 months) and older (16-18 months) male BALB/cJ mice. Exercised (EX) mice ran on a treadmill for 8 weeks at a gradually increasing speed and duration whereas control (CON) mice were only handled briefly during each exercise session and then returned to their cages. Mice were infected with herpes simplex virus type 1 (HSV-1) 24 h post-exercise. Serum IgM anti-HSV antibody, HSV-1 specific Th1/Th2 cytokine production by spleen cells, and cytokine production by alveolar cells were measured 7 days post-infection. In the aged mice, exercise was associated with an enhanced production of the HSV-1 specific Th1-associated cytokines, interleukin (IL)-2 and interferon (IFN)-gamma, but had no effect on the Th2-associated cytokine IL-10 or IgM antibody. No effect of exercise was observed in young mice. IL-12 production was not altered by exercise, but aging was associated with altered IL-12 production in a tissue-specific manner. In conclusion, moderate exercise was associated with increased antigen-specific IL-2 and IFN-gamma production in response to viral challenge in older mice.

Expression of Fas (CD95) and Fas ligand on peripheral blood mononuclear cells in critical illness and association with multiorgan dysfunction severity and survival.

OBJECTIVE: This was an exploratory study with three goals: a) to quantify the expression of the apoptotic receptor Fas and its ligand (FasL) on peripheral blood mononuclear cells (PBMCs) in patients with, or at risk for, multiple organ dysfunction syndrome (MODS); b) to compare this expression with the respective expression in matched controls; and c) to explore the association with MODS severity and survival. DESIGN: Repeated-measures correlational and cross-sectional design. SETTING: The surgical, medical, and the trauma/burn intensive care unit of an academic institution. PATIENTS: Thirty-five adult, critically ill patients meeting the diagnostic criteria for systemic inflammatory response syndrome (SIRS) with MODS, or at risk for MODS, were followed for 14 days. Thirty-five non-SIRS controls matched with patients for age, gender, and race comprised the control group. INTERVENTIONS: Peripheral blood sampling every 48 hrs. MEASUREMENTS/MAIN RESULTS: T cells were considerably depleted in SIRS/MODS patients (p <.001), and Fas and FasL expression on PBMCs (flow cytometric analysis) was elevated significantly compared with controls (p <.001). In contrast to controls, non-T cells were the major sources of Fas and FasL in SIRS/MODS patients (p <.01). Expression of Fas and FasL exhibited a bimodal correlation with severity (p <.03). High severity patients demonstrated increasing Fas and FasL expression with increasing severity in contrast to declining expression in moderately severe patients. Fas and FasL measurements were significantly and positively associated with the likelihood of survival (p <.05). CONCLUSIONS: Dysregulation in the expression of apoptotic receptors Fas and FasL, at least in PBMCs, may be involved in the pathophysiology of SIRS, the related lymphocytopenia, and the onset of MODS and the related morbidity and mortality rates.

Heart rate, neuroendocrine, and immunological reactivity in response to an acute laboratory stressor.

OBJECTIVE: The primary objective of the present study was to identify neuroendocrine and immunological correlates of cardiovascular reactivity to an acute laboratory stressor. METHODS: Subjects were 56 healthy volunteers. Heart rate and blood pressure were assessed at regular intervals during a 30-minute adaptation period and a 6-minute videotaped speech task. Blood was drawn before and after the task and was assayed for natural killer cell activity (NKCA), cortisol production, in vitro interferon gamma (IFN-gamma) and interleukin 10 production by peripheral blood mononuclear cells (PBMC), and antibody titers to the Epstein-Barr virus. Psychological measures were also administered. RESULTS: NKCA increased significantly in response to the task, and this increase was significantly and positively correlated with heart rate reactivity. IFN-gamma production by PBMC also increased in response to the task, but these increases were unrelated to heart rate reactivity. In addition, baseline cortisol levels were found to be predictive of heart rate reactivity. Finally, questionnaire data were modestly related to various aspects of stress-induced reactivity. CONCLUSIONS: Consistent with the task-related increases in NKCA and IFN-gamma, acute stress may signal an increase in at least some aspects of the cell-mediated, or TH1-driven, immune response. Furthermore, the finding that heart rate reactivity was related in part to baseline individual differences in cortisol production suggests that short-term cardiovascular responses to stress may be directly related to longer-term neuroendocrine modulation. Finally, the present results also help to highlight the influence of both sympathetic and nonsympathetic pathways in the response to acute stressors and suggest tentative links between certain psychological traits and various aspects of stress-induced reactivity.

Chemical sympathectomy increases the innate immune response and decreases the specific immune response in the spleen to infection with Listeria monocytogenes.

Many investigators have shown that ablation of the sympathetic nervous system (SNS) with 6-hydroxydopamine (6-OHDA) can alter cell-mediated and humoral immune responses to antigenic challenge. Fewer studies have examined 6-OHDA-induced changes in natural immunity. In this study, we have examined the effect of chemical sympathectomy on the nonspecific and specific phases of the response to infection with Listeria monocytogenes. Sympathectomy decreased splenic bacterial loads 3 and 5 days post-infection and increased splenic neutrophils 3 days post-infection. Sympathectomy decreased splenocyte numbers and antigen-stimulated cytokine secretion from splenocytes. These results suggest that the SNS influences specific responses by modulating innate responses.

Serum leptin levels are higher but are not independently associated with severity or mortality in the multiple organ dysfunction/systemic inflammatory response syndrome: a matched case control and a longitudinal study.

OBJECTIVE: Hypercatabolism and immune dysfunction are closely associated with the development of systemic inflammatory response--multiple organ dysfunction (SIRS/MODS) in critical illness. It remains unclear however, whether leptin, an adipocyte-derived hormone whose levels are influenced by several cytokines and which regulates immune function, food-intake and energy expenditure is independently related to the development of and/or severity and mortality from SIRS/MODS. DESIGN AND PATIENTS: To assess the role of leptin in SIRS/MODS we performed a matched case control and a longitudinal study (14 days) in 35 critically ill patients with SIRS/MODS and 35 matched controls. RESULTS: Baseline leptin levels were positively associated with body mass index (BMI) and TNF-alpha (P < 0.01) in patients and with IGF-1 and IL-6 levels (P < 0.05) in controls. Furthermore, leptin levels exhibited a progressive increase from the first to the last day of the study and although baseline levels were not different, peak leptin levels as well as leptin levels on the last day of the study were significantly higher in cases than in controls (P < 0.05). TNF-alpha levels, IL-6 and cortisol levels were also higher, whereas IGF-1 levels were lower in cases (P < 0.05). To assess whether leptin levels are independently associated with SIRS/MODS we performed multivariate logistic regression analysis which revealed that leptin up-regulation in cases is mediated by elevated TNF-alpha and cortisol levels. Finally, there was no independent association between leptin and survival in this group of critically ill patients. CONCLUSION: We conclude that cytokines and cortisol upregulate leptin levels, which may contribute to the development of the hypercatabolism, wasting and immune dysfunction but leptin levels are not independently associated with severity or mortality of patients with systemic inflammatory response-multiple organ dysfunction.

Prolonged exercise suppresses antigen-specific cytokine response to upper respiratory infection.

Fatiguing exercise has been associated with an increased susceptibility to infection. This study examined the antigen-specific T-helper (Th) type 1 and Th type 2 cytokine response to herpes simplex virus (HSV) infection after an acute bout of fatiguing exercise. Male BALB/cJ mice ran on a treadmill (Ex) until voluntary fatigue (approximately 2.5 h), and control mice were handled and remained next to the treadmill. Mice were infected with HSV 20 min after exercise. Mice were killed 2 or 7 days postinfection, and sera and spleens were taken for the determination of HSV-specific serum IgM, splenocyte cytokine production during culture with HSV, and splenocyte natural killer cell cytotoxicity. Both Th type 1 [interleukin (IL)-2, interferon-gamma, IL-12] and Th type 2 (IL-10) cytokine production in spleen cell cultures, as well as natural killer cell cytotoxicity, decreased in Ex on day 2 postinfection. On day 7 postinfection, there was no difference in HSV-specific serum IgM or cytokine production by cells from control and Ex mice, with the exception of decreased IL-12 in Ex mice. These findings suggest that fatiguing exercise may alter the kinetics of antigen-specific cytokine production.

Depression, medical illness, and interleukin-1beta in older cardiac patients.

OBJECTIVE: A model has been proposed in which atherosclerosis contributes to depression in later life by the effects of cytokines on central monoamine systems. We collected pilot data to test the hypothesis that interleukin-1beta (IL-1beta) is associated with depression in a cardiac patient group. METHOD: Thirty-seven subjects completed research evaluations that included depression diagnosis (Structured Clinical Interview for DSM-III-R), depressive symptom severity (Hamilton Rating Scale for Depression), medical illness burden (Cumulative Illness Rating Scale), and serum IL-1beta level measured by enzyme linked immunosorbent assay. RESULTS: Serum IL-1beta level was not significantly associated with depressive symptom severity or depression diagnosis, whether or not controlled for medical illness burden, age, and gender. IL-1beta level was significantly correlated with medical illness burden. CONCLUSIONS: We did not confirm our study hypothesis. The correlation of IL-1beta level with medical illness burden likely reflects its release as part of the "sickness response" in a wide variety of disease states. Further research using a larger sample size and a non-cardiac comparison group is warranted.

Soluble fas levels correlate with multiple organ dysfunction severity, survival and nitrate levels, but not with cellular apoptotic markers in critically ill patients.

Apoptosis is a mode of programmed cell death (PCD). Transduction of apoptotic signals results in cellular suicide. Organ specific apoptosis has been proposed as a factor in multiple organ dysfunction syndrome (MODS). Fas is a widely occurring apoptotic signal receptor molecule expressed by almost any type of cell, which is also released in a soluble circulating form (circulating fas, sfas). In this exploratory study, we investigated the association of sfas with severity, survival, known mediators of multiple organ dysfunction, and cellular apoptotic markers on peripheral blood mononuclear cells (PBMC) in a group of 35 patients with MODS and in 35 matched controls. Critically ill patients with MODS had significantly elevated sfas levels compared to controls over time (P < .001). Increased serum concentration of circulating fas was associated with increased severity of multiple organ dysfunction. Non-survivors exhibited significantly higher sfas levels compared to survivors (P < .01) and increasing sfas was inversely associated with the likelihood of survival (P < .05). Circulating fas levels correlated highly with serum nitrate concentration, but not with fas and fasL expression on PBMC of critically ill patients. TNF-alpha and IL-6, although they appear to be mediators of both apoptosis and MODS, had no association with sfas. These results are suggestive of the need for further investigation on the role of apoptotic signaling in the development of MODS. They also suggest a potential prognostic value of sfas for SIRS/MODS clinical outcomes.

Does programmed cell death (apoptosis) play a role in the development of multiple organ dysfunction in critically ill patients? a review and a theoretical framework.

OBJECTIVES: To critically review the current understanding of the pathophysiologic events leading to the development of secondary multiple organ dysfunction (MODS) in critical illness and to examine the role of apoptosis (programmed cell death) as a mechanism involved in the progression of MODS. DATA SOURCES: Research and review articles published since 1982 on the pathophysiology of MODS, particularly the role of cytokines, reactive oxygen species, heat shock proteins, and apoptosis. Research and review articles on the physiology of apoptosis. Articles include human/animal and in vitro/in vivo studies. DATA EXTRACTION: The most prevalent mediating factors of MODS were examined for their potential to induce apoptosis, as reported in the literature. The combination of several of the above factors was also examined in terms of apoptosis-triggering potential. DATA SYNTHESIS: Specific pathophysiologic conditions related to the onset of MODS have been shown to affect apoptotic rates in organ tissue cells and their respective endothelial cells in animal and in vitro models. These conditions include the following: a) increased release of inflammation-related cytokines; b) increased production of oxygen free radicals associated with ischemia/reperfusion injury and states of low tissue perfusion; c) expression and release of heat shock proteins from tissue cells and the liver; d) elevated glucocorticoid concentrations after adrenal cortex activation; and e) release of bacterial products into the systemic circulation. CONCLUSION: The most important MODS-related pathophysiologic conditions known to date have been shown to affect programmed cell death rates in almost all cell types. Organ-specific cell death involving both parenchymal and microvasculature endothelial cells is conceivably underlying organ dysfunction. The hypothesis that increased apoptotic rates are involved in organ dysfunction may provide a unifying theory for the pathophysiology of MODS.

A presurgical psychosocial intervention for breast cancer patients. psychological distress and the immune response.

OBJECTIVE: The present study evaluated the feasibility and potential immunological benefit of a presurgical intervention for breast cancer patients. METHODS: Forty-one newly diagnosed breast cancer patients were randomized into control (standard care) and intervention groups. In addition to standard care, intervention group members received a two-session psychosocial intervention. Blood was drawn at three timepoints: (1) at preintervention; (2) at postintervention/presurgery; and (3) at postsurgery. RESULTS: Examination of the immunological data revealed evidence of suppression of interferon-gamma (IFN-gamma) in the control group over time, but not in the intervention group. Secondary findings related to psychological assessment generally paralleled the IFN-gamma results. CONCLUSION: The relevance and applicability of these findings to future breast cancer intervention research is detailed.

Immune deviation following stress odor exposure: role of endogenous opioids.

Olfactory cues can alter immune function. BALB/c mice exposed to odors produced by footshock stressed donor mice have increased antibody responses and increased splenic interleukin (IL)-4 production following immunization relative to recipients of odors from unstressed animals. Here we document that exposure to stress odors results in analgesia that is blocked by the non-selective opioid receptor antagonist naltrexone. The stress odor-induced increase in antigen-driven IL-4 and antibody is also blocked by oral administration of naltrexone. Thus, we provide evidence that immune deviation can occur following a psychosocial stressor, and that the deviation appears to be mediated by endogenous opioid production.

Sympathectomy-induced immune changes are not abrogated by the glucocorticoid receptor blocker RU-486.

Removal of sympathetic noradrenergic input to the immune system by injection of 6-hydroxydopamine (6-OHDA) triggers increases in antigen-specific in vitro splenocyte proliferation and cytokine production in BALB/cJ and C57B1/6J mice. This examines the possible role of glucocorticoids in these previously reported changes. In both strains, chemical sympathectomy triggers an elevation of glucocorticoid levels immediately following injection of 6-OHDA, returning to normal within one to two days. In the BALB/cJ strain, glucocorticoid elevation is seen only after the initial 6-OHDA injection; levels in chronically denervated animals are not different from controls. In the C57B1/6J strain, the increase is seen even with chronically denervated animals. Prior implantation of mice with pellets containing the glucocorticoid receptor antagonist RU-486 does not abrogate denervation-induced increases in cytokine production or proliferation in either strain. In addition to the previously reported increased interleukin (IL)-2 and IL-4 production, there is an increase in IFN-gamma production in the C57B1/6J strain following either acute or chronic denervation. The persistence of denervation-induced changes even when the effect of corticosterone is blocked with RU-486 or diminished with chronic denervation indicates that the changes are driven mainly by a glucocorticoid-independent mechanism.

Central nervous system activation following peripheral chemical sympathectomy: implications for neural-immune interactions.

Many studies have demonstrated that ablation of the sympathetic nervous system (SNS) alters subsequent immune responses. Researchers have presumed that the altered immune responses are predominantly the result of the peripheral phenomenon of denervation. We, however, hypothesized that chemical sympathectomy will signal and activate the central nervous system (CNS). Activation of the CNS was determined by immunocytochemical visualization of Fos protein in brains from male C57BL/6 mice at 8, 24, and 48 h following denervation. A dramatic induction of Fos protein was found in the paraventricular nucleus (PVN) of the hypothalamus and other specific brain regions at 8 and 24 h compared to vehicle control mice. Dual-antigen labeling demonstrates that corticotrophin releasing factor (CRF)-containing neurons in the PVN are activated by chemical sympathectomy; however, neurons containing neurotransmitters which may modulate CRF neurons, such as vasopressin, tyrosine hydroxylase, and adrenocorticotropin, do not coexpress Fos. Our findings suggest an involvement of the CNS in sympathectomy-induced alterations of immunity.

Adrenal hormone modulation of type 1 and type 2 cytokine production by spleen cells: dexamethasone and dehydroepiandrosterone suppress interleukin-2, interleukin-4, and interferon-gamma production in vitro.

Our previous work has documented that physical or psychological stress can alter interleukin (IL)-2, IL-4, and interferon (IFN)-gamma production by spleen or lymph node cells in vitro. To determine if adrenal hormones might be mediating these stress-induced changes in type 1 and type 2 cytokines and immune effector functions, we cultured spleen cells in vitro with either the synthetic glucocorticoid dexamethasone (DEX) or the putative restorative hormone dehydroepiandrosterone (DHEA). Spleen cells were obtained from either young (5-6 weeks old) or mature (7-8 months old) BALB/c mice that were either unimmunized or immunized with the T-cell-dependent antigen keyhole limpet hemocyanin (KLH). We determined that DEX suppressed production of all three cytokines examined. DHEA was not associated with any enhancement of cytokine production. These data challenge the hypothesis that glucocorticoids can differentially regulate Th1-like versus Th2-like cytokine production. Further, they suggest that in stress paradigms in which differential regulation of cytokine production and effector function has been observed, other neuroendocrine factors in addition to glucocorticoids must be relevant.

Stressor-induced alterations in immune response and viral clearance following infection with herpes simplex virus-type 1 in BALB/c and C57B1/6 mice.

Extending earlier studies of stress-induced modulation of herpes simplex virus (HSV) infection and immunity, we investigated the effects of electric foot shock (0.3 mA) on cytokine production and immune effector function in response to a nonlethal inoculum of HSV-1 in two strains of inbred mice, C57B1/6 and BALB/c. Increased levels of infectious virus at the site of infection were observed in foot-shocked mice of both strains compared to control mice. The specific pattern of changes in interleukin (IL)-2 and interferon-gamma, as well as IL-4 and IL-10, induced by foot-shock stress differed between the two strains. IgM anti-HSV antibody responses were, however, increased in both strains.

Psychosocial influences on immune responses to HSV-1 infection in BALB/c mice.

The effects of differential housing (one or four mice/cage) on T-helper (Th) cell markers of cellular and humoral immune responses were examined. Differentially housed male BALB/cJ mice were infected with herpes simplex virus (HSV)-1 (Patton strain), and in vitro cytokine production [interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-gamma] by splenocytes and popliteal lymph node cells and serum antibody titers (IgM and IgG) were evaluated. Differential housing of male BALB/c mice influenced the magnitude, but not the kinetics, of some, but not all, immune responses to HSV-1. Splenocytes from individually housed mice produced more IL-2, IFN-gamma, IL-4, and IL-10 than splenocytes from group-housed mice; in popliteal lymph node cells, only IFN-gamma and IL-10 production was influenced by housing. Although the social environment influenced cytokine production, there were no concomitant changes in circulating IgM or IgG antibody titers. These results do not support the hypothesis that dominant Th cell responses are the primary targets of this psychosocial manipulation, or that a reciprocal relationship exists between Th1 and Th2 cell-derived cytokines.