Impaired natural killer cell activity during bereavement

Natural killer (NK) cell activity, a component of the immune surveillance system, was compared in women whose husbands had recently died with that found in age-matched women who had not experienced recent adverse life events. Bereaved women had significantly lower NK activity than women whose husbands were healthy. In a second study, depressive symptoms and NK activity were measured longitudinally in women before and after the death of their husbands. Our results suggest that depressive symptoms, not merely the death of the spouse, are related to a reduction in NK activity during bereavement.     

Depression, natural killer cell activity, and cortisol secretion

Natural killer (NK) cell activity was evaluated in 34 ambulatory patients with Major Depressive Disorder (MDD) and 21 healthy controls. No mean differences between the groups were found. However, female depressives (n = 19) exhibited higher NK activity than female controls (n = 14). The relationship between cortisol secretion and NK activity was examined using an integrated cortisol value derived from multiple blood samples taken between 1:00 and 4:00 PM. This comprehensive assessment of cortisol secretion circumvents spurious "single stick" cortisol values and provides a more accurate determination of hypercortisolemia than the dexamethasone suppression test. NK activity in depressives with cortisol hypersecretion (greater than 11 micrograms/dl) (n = 7) was no different than NK activity in depressives and controls with normal cortisol secretion. Furthermore, there was no correlation between cortisol secretion and NK activity in any of the groups. These results indicate that decreased NK activity is not a consistent finding in MDD and cannot be predicted by the presence of hypercortisolemia in these patients.     

Effect of endogenous cortisol levels on natural killer cell activity in healthy humans

The aim of this study was to examine the effects of increasing and decreasing endogenous cortisol levels on natural killer (NK) cell activity in vivo. Normal healthy volunteers participated in the following studies: baseline (n = 27), metyrapone challenge test (n = 10), dexamethasone suppression test (n = 10), and adrenocorticotropic hormone (ACTH) stimulation test (n = 8). Each subject served as his own control for each study. Each subject was tested for NK activity and plasma cortisol levels at 9 a.m., just before the challenge drug administration, and at 10 a.m., except for the dexamethasone study, in which only the 9 a.m. blood was drawn, 10 h after the dexamethasone administration. On the baseline study day, a significant decrease in plasma cortisol levels was found from 9 to 10 a.m. (p <.02) along with a significant increase in NK activity (p <.001). On the metyrapone test day, plasma cortisol levels at 10 a.m. were significantly reduced (p <.005) as expected, while NK activity at the same time point was not affected and was increased to an extent equivalent to the baseline study day. On the dexamethasone test day, plasma cortisol concentrations were significantly decreased (p <.0001) as compared to the same time point on the baseline day, without any significant change in the NK activity. On the ACTH test day, plasma cortisol rose significantly at 10 a.m. (p <.02), with no change in NK activity. We conclude that plasma cortisol alone has no significant effect on NK activity in vivo.     

Selective inhibition by alcohol and cortisol of natural killer cell activity of lymphocytes from cord blood

1. 1. The immunosuppressive effects of drugs such as alcohol or hormones such as cortisol may be age-related. To test this hypothesis, the authors investigated the in vitro effects of ethanol (EtOH) and cortisol on Natural Killer (NK) cell activity of lymphocytes from normal cord blood in comparison with that of lymphocytes from normal adult peripheral blood.

2. 2. K562, an erythroleukemia cell line, was used as a target in a 4 hr ⁵¹Cr release assay.

3. 3. Ethanol at 0.3% (V/V) and cortisol at 0.05, 0.1 and 0.2 μg/ml concentrations, added directly to a mixture of effector and target cells significantly suppressed the NK activity of cord blood lymphocytes in a dose dependent fashion, whereas similar concentrations of either EtOH or cortisol did not manifest significant immunoregulatory effects on NK cell activity of normal adult lymphocytes.

4. 4. Pre-treatment of the target with either EtOH or cortisol for 4 hours did not affect cytotoxicity. Inhibition of cytotoxicity was also not due to direct toxicity of effector cells because lymphocytes treated with either EtOH or cortisol showed normal ⁵¹Cr release and their viability was comparable to that of untreated control cells.

5. 5. This suggests a selective inhibitory effect of EtOH and cortisol on NK activity of neonatal lymphocytes that may be of clinical significance.

Plasma beta-endorphin and natural killer cell activity in major depression: a preliminary study.

Low concentrations of beta-endorphin have been found to enhance human natural killer (NK) cell activity in vitro. Both beta-endorphin and NK activity are changed by clinical depression. To evaluate whether circulating concentrations of beta-endorphin have a role in the in vivo modulation of cellular immunity in humans, we measured plasma beta-endorphin and NK cell activity in 14 depressed patients and 14 age-matched control subjects. In the depressed patients, both plasma beta-endorphin and NK cell activity were reduced to 76% and 57%, respectively, of the mean levels in the control subjects. In addition, beta-endorphin showed a significant positive correlation with lytic units of NK cell activity in the combined group of all subjects and in the patient group (p = 0.04), but not in the control group. The study supports the hypothesis that circulating endorphin is correlated with NK cell activity in vivo. This correlation may be higher in the depressed patient group.     

Influence of desmethylimipramine on natural killer cell activity

Mounting evidence suggests that the central nervous system (CNS) and the immune system are extensively interconnected. One question that arises is whether there is cross-reactivity between psychotropic agents, which are active in the CNS, and immune system function. To explore this notion, we examined the in vitro effect of the tricyclic antidepressant, desmethylimipramine (DMI), on human natural killer (NK) cell activity in seven separate experiments. At concentrations greater than or equal to 625 ng/ml, DMI reliably inhibited NK activity. Preincubation of lymphocytes with DMI before assay did not increase the inhibitory effect. Furthermore, removal of the drug from preincubated cells immediately before assay completely eliminated the inhibitory effect. These results demonstrate that DMI reversibly inhibits NK activity at serum concentrations that are not uncommonly found in depressed patients receiving this medication.     

Electroacupuncture up-regulates natural killer cell activity Identification of genes altering their expressions in electroacupuncture induced up-regulation of natural killer cell activity

As an important cellular component of the innate immune system, NK cells constitute a first line of defense against various infections and malignancies. Previous studies have reported electroacupuncture (EA) modulation of natural killer cell (NK cell) activities. Our study confirmed that EA treatment increases NK cell activity using (51)Cr release assay. Furthermore, in order to better understand the activation mechanism of NK cell by EA, we employed a cDNA microarray technique to elucidate how EA alters gene expressions in the spleen of rats. We screened EA responsive genes using a high-throughput screening and identified 154 genes. Among those genes we selected 4 genes that are known to play a crucial role in NK cell activation and examined their mRNA expressions after EA treatment using RT-PCR. Our data shows that EA treatment increased CD94, PTK and VCAM-1 expressions while decreased PTP and SHP-1. These results imply that EA treatment increase PTK expression, which increases NK cell activity, through induction of CD94 while decreases SHP-1, which inhibits NK cell activity, simultaneously so that it activates NK cell with high efficacy. It seems that increased VCAM-1 expression is due to INF-gamma produced by activated NK cell. Increased production of VCAM-1 is expected to play an important role in binding of NK cell to the target cell. The result of our study may provide key insights in understanding the mechanisms of activation of NK cell induced by EA.     

Reward linked to increased natural killer cell activity in rats

In rats splenic natural killer (NK) cell activity was found to be significantly higher following chronic uncontrollable electrical stimulation of the lateral hypothalamus in fully conscious rats, compared to sham-operated rats. In a pre-test study, all rats had demonstrated that the electrode site had self-stimulating properties, which supports the possibility that the experience of reward may be implicated in NK cell activity augmentation.     

Norepinephrine inhibits human natural killer cell activity in vitro.

The effect of norepinephrine on human NK cell activity was investigated using a flow cytometry assay. NK cell activity was found to be inhibited by direct addition of norepinephrine to lymphocyte/target cell mixtures in a dose-dependent fashion. This inhibitory effect of norepinephrine was blocked by propranolol but not by atenolol. The results suggest that norepinephrine has a negative influence on NK cell activity and that the effect of norepinephrine is mediated via beta 2-adrenoceptors.     

Altered populations of natural killer cell and natural killer T cell subclasses in myasthenia gravis

Since the innate immune system can influence the disease activity of myasthenia gravis (MG), such as during infection, the frequencies of natural killer (NK) cells and NKT cells were analyzed in the blood and thymus. Before therapy (thymectomy plus glucocorticoid), the MG patients with thymic hyperplasia, but not those with thymoma, showed increased frequencies of mature NKT cells (CD3(+)TCRV(alpha)24(+)CD161(bright)) in the blood, while the frequency of immature NKT cells was unaltered. In the blood of the patients with thymoma, but not those with hyperplasia, the frequency of cytotoxic subclass of NK cells (CD3(-)CD16(+)CD56(dim)) was lower than that of the control. These alterations returned to normal after therapy. The thymic frequencies of NKT cells and NK cells in MG thymuses were unaltered. These results suggest the involvement of both innate and acquired immunity in the disease activity of MG.     

Acute effect of qi-training on natural killer cell subsets and cytotoxic activity

This study assesses the effects of Qi-training on natural killer cell cytotoxicity. Nine experimental subjects did 1 h of Qi-training, and 9 control subjects relaxed during the same time. Natural killer cell cytotoxicity increased 60% immediately after Qi-training (p<.01) and returned to the basal level within 2 h after training. Natural killer cell subset number did not change after Qi-training. Natural killer cell cytotoxicity and cell number were not significantly correlated. These data suggest that Qi-training has an acute stimulatory effect on natural killer cell activity, but has no effect on phenotypical changes in the natural killer cell subset.     

Corticotropin-releasing hormone augments natural killer cell activity through a naloxone-sensitive pathway

Overnight treatment of murine leukocytes with corticotropin-releasing hormone (CRH) and arginine vasopressin enhances natural killer cell activity. Moreover, the opioid receptor antagonist, naloxone, as well as the delta-class opioid receptor antagonist, naltrindole, can block this effect. The responsivity of murine leukocytes to CRH is both dose- and time-dependent. The effector cells are both MAC-1 and Thy-1.2 antigen-positive. Whereas beta-endorphin is also shown to enhance natural killer cell activity in a naloxone-reversible manner, adrenocorticotropic hormone (ACTH) has a negligible effect. Macrophage depletion prior to incubation with CRH blocks the CRH-induced natural killer cell augmentation. These results suggest hypothalamic-releasing hormones such as CRH may have a biologically relevant role in the modulation of immune cells either directly or indirectly through the induction of neuropeptide hormones known to have immunomodulatory capabilities.     

海洛因依赖者脱毒后自然杀伤细胞活性的变化

目的　探讨海洛因依赖者在脱毒后自然杀伤（ Ｎ Ｋ） 细胞活性是否恢复正常。方法　将１８ 例脱毒４８ ～７２ 小时、１８ 例脱毒３３ ～５８ 天、１５ 例脱毒１１７ ～１２０ 天的海洛因依赖者及１１ 名正常对照者纳入研究。 Ｎ Ｋ 细胞活性采用四甲基偶氮唑盐（ Ｍ Ｔ Ｔ） 比色分析法测定。结果　海洛因脱毒后４８ ～７２ 小时、３３ ～５８ 天、１１７ ～１２０ 天及正常对照组的 Ｎ Ｋ 细胞活性分别为３０１１ ％ 、３４２５ ％ 、３８９７ ％ 、４４８９ ％ 。与正常对照组比较,海洛因依赖者脱毒后４ 个月内的 Ｎ Ｋ 细胞活性减少（ Ｐ＜ ００１） 。海洛因依赖者随脱毒时间延长, Ｎ Ｋ 细胞活性有逐步恢复的趋势, Ｎ Ｋ 细胞活性减少与戒断症状或稽延性戒断症状无相关关系。结论　完全脱毒４ 个月的海洛因依赖者的免疫功能未能恢复至正常水平。     

Reduced natural killer cell activity in major depression: neuroendocrine implications

Natural killer cell activity (NKCA) was significantly reduced in a group of depressed patients, melancholic subtype, compared to sex- and age-matched controls. Corticotropin and cortisol values were significantly higher in the depressed subjects than in the controls, but no correlation between high hormone levels and low immunological activity was found in the patients.     

Mating suppresses splenic natural killer cell activity in male golden hamsters

The possibility that sexual behavior is associated with changes in natural killer cell activity was explored using a 4-h chromium-51 release assay. Mated male Golden Hamsters (Mesocricetus auratus) showed a significant suppression of natural killer cell activity 2 h after sexual activity relative to matched Virgin controls. Natural killer cell activity returned to control levels by 16 h postmating. The suppression of natural killer cell activity did not correlate with changes in plasma cortisol, transcortin, or testosterone levels, or with ejaculatory or intromissive behaviors. Administration of 0.40 mg/100 g of testosterone also suppressed natural killer activity at 2 h.     

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.     

Dissociation of inflammatory markers and natural killer cell activity in major depressive disorder

Major depressive disorder is associated with increases in infectious disease risk as well as the incidence of inflammatory disorders. Declines of natural killer (NK) cell activity are reliably found in depression, whereas other studies report evidence of inflammation in depressed patients. The potential association between NK activity and circulating markers of immune activation has not been previously examined in the context of major depression. In this study, we measured levels of NK activity, circulating levels of interleukin-6 (IL-6), soluble interleukin-2 receptor, and acute phase proteins in 25 male patients with current major depressive disorder and 25 age, gender, and body weight comparable controls. As compared to controls, patients with major depressive disorder showed lower NK activity (p = .05) and higher circulating levels of IL-6 (p < .05). Levels of NK activity were not correlated with IL-6 or with other markers of immune activation. The independent effect of depression on inflammatory markers and natural killer immune responses has implications for understanding individual differences in the adverse health effects of major depressive disorder.