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PubMed1998

IL-6 knock-out mice show modified basal immune functions, but normal immune responses to stress.

To better determine the role of interleukin-6 in the mechanisms that regulate stress-induced immunosuppression, we used in this study an interleukin-6-deficient mice model recently generated by gene targeting. We report here that, in basal conditions, mutant mice are characterized by altered immune functions. Natural killer activity and interleukin-2 production are lower in splenocytes of interleukin-6 deficient mice compared to those of controls, whereas Concanavalin A-induced splenocyte proliferation is comparable with that observed in wild-type mice. Moreover, splenocyte concentrations of the immunosuppressive opioid peptide beta-endorphin are higher in interleukin-6 deficient mice while serum corticosterone concentrations are unchanged. After exposure to 16 h of restraint stress, a significant suppression of the immune parameters is exhibited and a significant increase of splenocyte beta-endorphin concentrations are present in knock-out and normal animals. Finally, corticosterone is normally induced in stressed interleukin-6-deficient mice, thus demonstrating that interleukin-6 is not crucial for the activation of the hypothalamic-pituitary-adrenal axis. In conclusion, our results indicate that interleukin-6 is not a key factor in the immunosuppression observed after restraint stress.

Animals↗
PubMed1998

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.

Adrenocorticotropic Hormone↗
PubMed1998

Human brain-immune relationships: a PET study.

To study brain-immune relations, we correlated positron emission tomographic (PET) measures of regional cerebral blood flow (rCBF) with immune measures in 10 female volunteers. The natural killer (NK) activity correlated negatively with activity bilaterally in the secondary sensory cortex, whereas the Concanavalin A (Con A) response correlated positively with rCBF bilaterally in secondary visual, motor, and sensory cortices, the thalamus, the putamen, and the left hippocampus. Although representing preliminary data from a small number of subjects, these observations provide further support for the presence of interactions between the brain and the immune system.

Adult↗
PubMed1998

Role of serotonin in the immune system and in neuroimmune interactions.

Serotonin (5-HT) is one of the most extensively studied neurotransmitters of the central nervous system. 5-HT is, however, also present in a variety of peripheral tissues including in constituents of the immune system. The function of 5-HT in the immune system has received increasing attention since about 1984, but has been reviewed only once, in 1985. In recent years, modern techniques of molecular biology such as reverse-transcriptase polymerase chain reaction and targeted gene disruption have made it possible to study new important aspects of 5-HT in the immune system. In the first part of the review, we explore whether 5-HT is involved in interactions between the central nervous and immune systems. It emerges that 5-HT may mediate interactions of these two systems by four different pathways. In the second part, we dissect the functional roles of 5-HT in the immune system. We describe the distribution of 5-HT receptors and the 5-HT transporter on immune cells and estimate which levels 5-HT may attain in the extracellular space in physiological conditions and under pathological circumstances such as inflammation, thrombosis, and ischemia. At these 5-HT concentrations, four major functions for 5-HT emerge. These include T cell and natural killer cell activation, delayed-type hypersensitivity responses, production of chemotactic factors, and natural immunity delivered by macrophages. Finally, we discuss promising future avenues to further advance knowledge of the role of 5-HT in the immune system and in neuroimmune interactions.

Animals↗
PubMed1999

Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: A link to neurogenic skin disorders.

Many skin disorders, such as atopic dermatitis and psoriasis, worsen during stress and are associated with increased numbers and activation of mast cells which release vasoactive, nociceptive, and proinflammatory mediators. Nontraumatic acute psychological stress by immobilization has been shown to induce mast cell degranulation in the rat dura and colon. Moreover, intradermal injection of corticotropin-releasing hormone (CRH) or its analogue urocortin (10(-5)-10(-7) M) induced skin mast cell degranulation and increased vascular permeability. Here, we investigated the effect of acute immobilization stress on skin mast cell degranulation by light microscopy and electron microscopy. Immobilization for 30 min resulted (P < 0.05) in degranulation of 40.7 +/- 9.1% of skin mast cells compared to 22.2 +/- 7.3% in controls killed by CO(2) or 17.8 +/- 2.4% in controls killed by pentobarbital. Pretreatment intraperitoneally (ip) with antiserum to CRH for 60 min prior to stress reduced (P < 0.05) skin mast cell degranulation to 21.0 +/- 3. 3%. Pretreatment with the neurotensin (NT) receptor antagonist SR48692 reduced (P < 0.05) mast cell degranulation to 12.5 +/- 3.4%, which was significantly (P < 0.05) below control levels. In animals treated neonatally with capsaicin to deplete their sensory neurons of their neuropeptides, such as substance P (SP), mast cell degranulation due to immobilization stress was reduced to about 15%. This is the first time that stress has been shown to trigger skin mast cell degranulation, an action not only dependent on CRH, but apparently also involving NT and SP. These findings may have implications for the pathophysiology and possible therapy of neuroinflammatory skin disorders such as atopic dermatitis, neurogenic pruritus, or psoriasis, which are induced or exacerbated by stress.

Acute Disease↗
PubMed1999

The differential impact of training stress and final examination stress on herpesvirus latency at the United States Military Academy at West Point.

In this study, we searched for evidence for reactivation of three latent herpesviruses, Epstein-Barr virus (EBV), herpes simplex virus type-1 (HSV-1), and human herpesvirus 6 (HHV-6), in West Point cadets experiencing two different stressors. Blood samples were obtained from cadets before and after a 6-week training period known as "Cadet Basic Training" (CBT), at a baseline prior to final examinations, and then once again during the week of final examinations. Antibody titers to latent HSV-1, EBV, and HHV-6 were determined as a measure of the steady-state expression of latent virus. EBV virus capsid antigen (VCA) IgG antibody titers were unchanged in blood samples obtained prior to and immediately after CBT. However, EBV antibody titers were significantly higher in the blood sample obtained during examination week than in the baseline period before examination; they were also higher than antibody titers before/after CBT. None of the serum samples were positive for EBV VCA IgM antibodies, indicating that the changes in antibody titers to EBV were not associated with recent EBV infections in the class. No significant changes in antibody titers to HSV-1 or HSV-6 were found over the identical time periods, including examination week. Academic stress but not CBT modulated the steady-state expression of latent EBV, resulting in the reactivation of latent virus. The same stressors, however, did not affect the steady-state expression of latent HSV-1 or HSV-6, at least as measured by changes in antibody titers. The data provide additional evidence of the impact of different psychological stressors on the steady-state expression of latent herpesviruses.

Adult↗
PubMed2001

Behavioral effects of infection with IL-6 adenovector.

The onset of autoimmunity in lupus-prone mice is accompanied by a constellation of behavioral deficits, termed Autoimmunity-Associated Behavioral Syndrome (AABS). In particular, a spontaneous increase in serum interleukin-6 (IL-6) levels in five-week old MRL-lpr mice coincides temporally with blunted responsiveness to sucrose and excessive immobility in the forced swim test. These relationships, along with evidence that sucrose intake drops after systemic IL-6 overexpression is induced in healthy mice, have led to the hypothesis that sustained elevation in serum IL-6 also induces other aspects of AABS. This hypothesis is tested by comparing the behavioral profiles of healthy mice infected with Ad5mIL6 adenovirus (2 x 10(8) pfu of virus/mouse i.p.) with those of animals infected with control Ad5 virus. This methodology was used to achieve high circulating levels of IL-6, to overcome the problem of its short half-life, and to avoid the stressful effects of repeated injections. The Ad5mIL6 infection (known to induce excessive IL-6 levels over five days) transiently reduced food, water, and sucrose intake, as well as rectal temperature in MRL +/+ and AKR/J mice. Although the level of locomotor activity did not decline, Ad5mIL6-infected AKR/J mice demonstrated less novel object exploration. Performance in the step-down, plus-maze, and spontaneous alternation tests were disturbed to various degrees in all infected animals. The present results suggest that prolonged exposure to circulating IL-6 primarily impairs ingestive behavior, likely reflecting enhanced catabolism. The inability of circulating IL-6 to alter other aspects of behavior supports the hypothesis that multiple immuno-neuroendocrine mechanisms contribute to the pathogenesis of AABS.

Adenoviridae↗
PubMed2001

Central CRH suppresses specific antibody responses: effects of beta-adrenoceptor antagonism and adrenalectomy.

Central corticotropin releasing hormone (CRH)-induced activation of the sympathetic nervous system and/or the pituitary-adrenal axis is hypothesized to mediate suppression of in vivo specific antibody responses. To test whether beta-adrenergic receptor activation is involved in the immunosuppressive effects of central CRH, rats were pretreated with propranolol or saline before intracerebroventricular infusion of CRH and immunization with keyhole limpet hemocyanin (KLH). KLH (3 microg/kg) immunization induced significant increases in circulating levels of antigen-specific IgM and IgG. Central infusion of CRH (200 pmol) suppressed both IgM and IgG responses. Pretreatment with propranolol (20 mg/kg IP) reversed CRH-induced suppression of IgG responses but had no effect on IgM levels. To test whether adrenal activation also plays a role in the effects of KLH on specific antibody responses, a separate group of animals underwent adrenalectomy prior to CRH infusion and immunization with KLH. As compared to nonadrenalectomized control rats, adrenalectomized rats showed a reduction of antibody responses, and CRH failed to induce a further suppression of IgM or IgG responses in adrenalectomized animals. Collectively, these data suggest that beta-adrenoceptors mediate the suppression of primary antibody responses induced by central CRH. Moreover, the adrenals may promote optimal primary antibody responses after exposure to physiological levels of antigen.

Adjuvants, Immunologic↗
PubMed2001

Stress-induced changes in peripheral natural killer cell cytotoxicity in pigs may not depend on plasma cortisol.

The study examined cortisol (COR) involvement in stress-related changes in natural killer cell cytotoxicity (NKCC). The relationship between blood COR level, phasic changes in NKCC, and the number of large granular lymphocytes (LGL) was examined in pigs during the course of 4-h immobilization stress (IMB) and for 6 days after its termination. NKCC was determined using 18-h 51Cr-release assay, LGL number was assessed with a standard hematological method, and plasma COR level was measured by radioimmunoassay. The blood level of COR was increasing during IMB (max 446Delta% at the second hour) and decreased after its termination (max -59Delta% on day 2). Changes in NKCC level and LGL number were biphasic; i.e., an initial increase in both measures (NKCC max 24Delta%, LGL max 18Delta%) in an early phase of stress (0-1h) was followed by their subsequent decrease (NKCC max -35Delta%, LGL max -41Delta%) in the late phase (3-4 h) of stress, which persisted for several days after termination of IMB. Thus, in the early phase of stress, there was a positive correlation between NKCC, LGL number, and COR levels (all elevated); a positive correlation between the measures also occurred after termination of IMB (all decreased). A negative correlation between COR and NKCC, which might be indicative of COR-related immunosuppression, was found only in the late (3-4 h) phase of stress. It is concluded that COR may be only one of multiple factors (possibly antagonistic) determining an actual immune response during stress.

Animals↗
PubMed2001

Aberrant nuclear expression of AP-1 and NFkappaB in lymphocytes of women stressed by the experience of breast biopsy.

We have investigated the expression of AP-1 and NFkappaB in peripheral blood lymphocytes of women scheduled for breast biopsy. Samples were collected when women were informed of the need for biopsy (prebiopsy, T1, 5-7 days prior to the actual biopsy) and 7-10 days after they learned the result of their biopsy (postbiopsy, T2). At the time of blood collection, psychological stress was evaluated using Speilberger's State Trait Anxiety Inventory (STAI) and the Profile of Mood States (POMS). Women scheduled to undergo breast biopsy reported significant increases in anxiety (STAI) and mood disturbance (POMS). Gel shift mobility assays showed that mitogen stimulated peripheral blood lymphocytes of these women were less capable of the nuclear expression of AP-1 or NFkappaB at T1. Similar assessments, 7-10 days after the women learned of the results of their breast biopsy, showed these same women to have a marked reduction in anxiety and mood disturbance and an increased nuclear translocation of AP-1 and NFkappaB. These results show a significant decrease in nuclear AP-1 and NFkappaB expression during the period of emotional distress prior to biopsy with a return of nuclear transcription activity to normal levels when distress was relieved. Several studies have correlated increased psychological stress with decreased immune function. The results of this study suggest that psychological stress may mediate immunosuppression by altering the expression of the transcription factors, AP-1 and NFkappaB.

Biopsy↗
PubMed2001

Involvement of central, but not placental corticotropin releasing hormone (CRH) in heat stress induced immunosuppression during pregnancy.

To clarify whether corticotropin releasing hormone (CRH) and beta-endorphin (betaEP) system mediate maternal immunosuppression in pregnant rats exposed to heat through central or placental pathway, we examined the effects of intravenous (iv) (100 or 500 microg) or intracerebroventricular (icv) (5 microg) administration of CRH receptor antagonist alpha-helical CRH (9-41) on splenic natural killer cell activity (NKCA) as well as betaEP in blood, pituitary lobes, and placenta in pregnant rats at 15 to 16 days gestation. Two-way ANOVA revealed that heat reduced NKCA and elevated blood and pituitary betaEP but did not change placental betaEP. Iv administered 500 microg and icv administered alpha-helical CRH reversed the reduced NKCA and the elevated pituitary betaEP, while iv administration of 100 microg alpha-helical CRH did not. The increased blood betaEP was reversed by iv 100 and 500 microg alpha-helical CRH and icv administration. Both iv and icv administrations reduced placental betaEP independent of heat exposure. Thus, the response of placental betaEP to iv administration of alpha-helical CRH seemed to be stronger than that of pituitary betaEP. These results indicate that alpha-helical CRH which acts on pituitary betaEP antagonizes heat-induced immunosuppression during pregnancy, suggesting that immunosuppression produced by heat stress during pregnancy is mediated by the central CRH system. The placental CRH-betaEP system seems unlikely to be involved in the immunosuppression. Physiologic roles of placental CRH and opioid system should be clarified by future in vitro experiments using placenta specimen including placental immunocyte.

Animals↗
PubMed2001

Altered functional responses with preserved morphology of gonadotrophic cells in congenitally athymic mice.

Neonatal thymectomy or congenital absence of the thymus induces severe reproductive deficiencies in female mice, which are associated with reduced levels of circulating and pituitary gonadotropins. In contrast, the reproductive function is well preserved in nude males. It was therefore of interest to assess gonadotrophic cell morphology and function in congenitally athymic male mice. Circulating gonadotropins were measured under basal and stressful conditions, taking as a reference their haired counterparts. Adult normal (+/+), heterozygous nude (nu/+), and homozygous (nu/nu) CD-1 mice were subjected to 1-h immobilization stress. Serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were assessed by RIA at 0, 30, and 60 min poststress. Athymic animals showed significantly lower basal levels of serum LH and FSH than their heterozygous littermates. Immunohistochemical assessment of LH and FSH cell populations revealed a normal morphology and cell number in the athymic animals compared to their normal littermates. Immobilization stress induced a significant reduction in gonadotrophin levels, particularly LH, in normal mice but had only a weak effect in athymic animals. It is concluded that congenital athymia in the adult male mouse is associated with decreased basal levels of serum LH and FSH, in the presence of a normal gonadotroph number and morphology. The anomalous responses of athymic mice to stress do not appear to be due to primary hypopituitarism but, rather, to an altered modulation of pituitary hormone secretion. .

Animals↗
PubMed2001

Peripheral blood natural killer cell cytotoxicity after damage to the limbic system in the rat.

The present work was aimed at examining the possible involvement of different parts of the septal area (dorsal, medial, lateral, and septohypothalamic nucleus), the basolateral amygdala, and the bed nucleus of the stria terminalis (BNST) in the regulation of the cytotoxic activity of NK cells (NKCC). The experimental approach included performing electrolytic (or sham) lesions in the tested brain areas and to measuring the peripheral blood NKCC (chromium-51 release assay), the number of leukocytes and lymphocytes, and the plasma corticosterone levels both before and at different time points after the lesion. Lesions were also induced in the three extralimbic structures: the paraventricular hypothalamic nucleus (PVN), the dorsal caudate-putamen, and the cerebellum. To test for a possible effect on NKCC of stress associated with blood collection, anesthesia, cranial surgery, and passing electric current through the brain the proper control experiments were also performed. Lesions of the medial septum and BNST caused gradual depression of NKCC, which peaked on the 10th day after the lesion, followed by a recovery to the baseline on days 21 (medial septum) and 42 (BNST) postinjury. In the respective sham-lesioned groups, mere insertion of electrodes into the medial septum and BNST evoked transient enhancement of NKCC (on the 3rd postlesion day), probably resulting from mechanical stimulation of the nervous tissue. Destruction of the other limbic and extralimbic structures appeared ineffective. After PVN lesions NKCC remained unchanged, despite an approximately 60% decrease in the basal corticosterone level. No adverse effects of the experimental and surgical procedures on NKCC, leukocyte and lymphocyte number, and corticosterone level were found, indicating that electrolytic lesions and other stereotaxic techniques can be safely used to study the brain-immune system interactions. The results obtained raise the question about the interrelationship between the medial septum and the hippocampal formation, BNST, the medial amygdala, and the hypothalamus (both medial and lateral) as a possible circuit involved in the regulation of cellular immune functions.

Amygdala↗
PubMed2000

Cytokine production by naive and primary effector CD4+ T cells exposed to norepinephrine.

We recently showed that clones of Th1 cells, but not Th2 cells, expressed a functional beta-2-adrenergic receptor (beta2AR) and that either norepinephrine or the beta2AR agonist terbutaline stimulated this receptor to modulate the level of Th1 cytokines produced. In the present study, we show that norepinephrine and terbutaline stimulate the beta2AR to decrease the level of IL-2 produced by freshly isolated murine splenic naive CD4+ T cells from either Balb/C or DO11.10 transgenic mice and activated polyclonally with anti-CD3 and anti-CD28 mAbs. In contrast, the level of cytokines produced by primary effector Th1 and Th2 cells were unaffected when norepinephrine, terbutaline, or cAMP analogs were added at the time of restimulation. These results suggest that a diversity exists among CD4+ T-cell subsets with respect to the level of adrenergic receptor expression, responsiveness to cAMP, stage of cell differentiation, or a combination of the above.

Adrenergic beta-Agonists↗
PubMed2000

Restraint-induced modulation of allergic and irritant contact dermatitis in male and female B6.129 mice.

Recent studies in rats have indicated that acute restraint enhances cutaneous hypersensitivity. We hypothesized that acute restraint would also modulate the development of allergic and irritant dermatitis in mice and that these restraint-induced changes would be reflected in the cutaneous cytokine profile and be gender-specific. For these studies, male and female B6.129 mice were sensitized and challenged with the contact sensitizer dinitrofluorobenzene or challenged with the irritant croton oil. Two-hour restraint was applied prior to chemical challenge. Restraint combined with chemical increased ear swelling in both genders in ACD, a change that was blocked by administration of RU-486 prior to restraint. Neither restraint nor RU-486 administration modulated development of ICD; however, IL-1beta was decreased by restraint in females only. TNF-alpha and IFN-gamma production were modified in ACD; TNF-alpha in both genders and IFN-gamma in female mice only. Our data demonstrate that acute restraint increases serum corticosterone in B6.129 male and female mice to comparable levels. Restraint modulated the murine ear swelling in ACD, but not ICD, in both genders, and the change in the ear swelling response and cytokine production were, at least in part, corticosterone-dependent.

Animals↗
PubMed2000

Quantitative analysis of the neuroendocrine-immune axis: linear modeling of the effects of exogenous corticosterone and restraint stress on lymphocyte subpopulations in the spleen and thymus in female B6C3F1 mice.

The effects of exogenous corticosterone and restraint stress on the number and percentage of lymphocyte subpopulations in the spleen and thymus were evaluated. The data were used to generate linear models that describe the relationship between these parameters and the area under the corticosterone concentration vs time curve (AUC). Comparison of the models revealed that the number of nucleated cells in the spleen was decreased similarly by exogenous corticosterone and restraint (at equivalent corticosterone AUC values). However, exogenous corticosterone caused a greater decrease in cell number in the thymus than it did in the spleen. Corticosterone preferentially depleted CD4+CD8+ cells in the thymus, whereas the same corticosterone exposure produced by restraint stress did not. In the spleen, cell number for all major cell types was decreased by both treatments, but there were minor differences in the change in percentage of some subpopulations induced by exogenous corticosterone as compared to restraint. The models derived here provide quantitative data that indicate the magnitude of corticosterone and stress-induced effects on lymphocyte populations in the spleen and thymus. These results have mechanistic implications, and they may be useful in future efforts to extrapolate from mouse to human by completing a risk assessment parallelogram.

Animals↗