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      Suppression of NK Cell Activity and of Resistance to Metastasis by Stress: A Role for Adrenal Catecholamines and β-Adrenoceptors

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          Although acute stress has been reported to suppress natural killer cell activity (NKA) and host resistance to metastasis, it is unclear whether the sympathetic nervous system (SNS) has a role in these effects. The current study in Fischer 344 rats assessed the involvement of adrenal catecholamines and β<sub>1</sub>- and β<sub>2</sub>-adrenoceptors in mediating these deleterious effects of swim stress. In addition to assessing the number and activity of NK cells following swim stress, we used a tumor model based on the MADB106 mammary adenocarcinoma line: this syngeneic tumor metastasizes only to the lungs, and its lung tumor retention (LTR) and metastatic colonization are highly sensitive to NKA. The findings indicate that stress increased both LTR, assessed 24 h after inoculation, and the number of lung metastases, counted 3 weeks later. These effects were attenuated or completely abolished by the ganglionic blocker chlorisondamine (3 mg/kg i.p.), by adrenal demedullation, by a selective β-adrenergic antagonist (nadolol, 0.4 mg/kg), and additively by a selective β<sub>1</sub>- (atenolol, 1–6 mg/kg) and a selective β<sub>2</sub>-antagonist (either butoxamine 4–32 mg/kg or ICI-118,551 0.3–8 mg/kg). Stress also suppressed NKA, and adrenal demedullation prevented this suppression. Administration of adrenaline (0.1–1 mg/kg) or of a β-adrenergic agonist (metaproterenol, 0.8 mg/kg), in physiologically relevant doses, suppressed NKA in a dose-dependent manner, and increased LTR to levels characteristic of swim stress. Taken together, these findings suggest that acute stress, by releasing catecholamines from the adrenal glands and activating β<sub>1</sub>- and β<sub>2</sub>-adrenoceptors, suppresses NKA and consequently compromises resistance to NK-sensitive metastasis.

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          Most cited references 9

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          Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity.

           G Page,  G Shakhar,  S Eliyahu (1999)
          Stress and surgery have been suggested to compromise host resistance to infectious and malignant diseases in experimental and clinical settings. Because stress affects numerous physiological systems, the role of the immune system in mediating such effects is unclear. In the current study, we assessed the degree to which stress-induced alterations in natural killer (NK) cell activity underlie increased susceptibility to tumor development in F344 rats. Two stress paradigms were used: forced swim and abdominal surgery. Host resistance to tumor development was studied using 3 tumor models syngeneic to inbred F344 rats: CRNK-16 leukemia and the MADB106 mammary adenocarcinoma, both sensitive to NK activity, and the NK-insensitive C4047 colon cancer. Swim stress increased CRNK-16-associated mortality and metastatic development of MADB106 but not metastasis of C4047 cells. In both stress paradigms, stress suppressed NK activity (NKA) for a duration that paralleled its metastasis-enhancing effects on the MADB106 tumor. In vivo depletion of large granular lymphocyte/NK cells abolished the metastasis-enhancing effects of swim stress but not of surgical stress. Our findings indicate that stress-induced suppression of NKA is sufficient to cause enhanced tumor development. Under certain stressful conditions, suppression of NKA is the primary mediator of the tumor-enhancing effects of stress, while under other conditions, additional factors play a significant role. Clinical circumstances in which surgical stress may induce enhanced metastatic growth are discussed.
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            Natural killer cells and cancer.

            Natural cytotoxicity, mediated by natural killer (NK) cells and cell with lymphokine-activated killer (LAK) activity, is believed to play an important role in host anti-cancer mechanisms. The authors critically review recent publications on the role of natural cytotoxicity in patients with cancer. In patients with cancer, several studies have noted variations in the numbers and activity of NK and cells with LAK activity in different body compartments. NK cell activity in the peripheral blood lymphocytes (PBLs) is higher than that found in lymph nodes and within tumors, and this appears to be due to the presence of suppressor factors. The natural cytotoxicity of PBLs in patients with different types of cancers varies. However, there appears to be a trend for natural cytotoxicity to be reduced in certain cancer patients, possibly related to tumor volume or dissemination. Anti-cancer treatments (e.g., surgery, hormonal modulation, radiotherapy and chemotherapy) can also result in suppression of natural cytotoxicity, although the long-term effect on response to treatment and development of metastases is at present unknown. NK and LAK cells, through the use of immune biologic modifiers, have been demonstrated to have a therapeutic role in the treatment of human cancers. Further studies are required to determine the optimal dosages and combinations of chemotherapeutic agents, the timing of surgery, and the adjuvant use of immune biologic response modifiers. An increasing awareness and understanding of this field, may allow for the future development of anti-cancer therapies.
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              Acute alcohol intoxication suppresses natural killer cell activity and promotes tumor metastasis.

              Alcohol consumption is associated with increased morbidity and mortality related to infectious diseases and malignancy (1-5), although immune mediation of these relationships is controversial. Specifically, the activity of natural killer (NK) cells, which are involved in the resistance to infections and metastasis, can be suppressed in the presence of ethanol in vitro. However, acute consumption or infusion of ethanol in vivo exerts no effects on NK activity assessed in vitro thereafter. Therefore, we have developed and used a method to study the effects of ethanol on NK activity in living rats by using an NK-sensitive metastatic process and selective depletion of NK cells in vivo. Acute ethanol intoxication caused a marked suppression of NK activity in vivo and a tenfold increase in the number of MADB106 tumor metastases. Ethanol had no effect in rats selectively depleted of NK cells or when an NK-insensitive tumor (C4047) was used. These findings suggest that even acute ethanol intoxication markedly suppresses NK activity in the living organism. This suppression may underlie some aspects of the association between alcoholism, infectious disease and malignancies.

                Author and article information

                S. Karger AG
                December 2000
                15 December 2000
                : 8
                : 3
                : 154-164
                aDepartment of Psychology, Tel Aviv University, Tel Aviv, Israel, bSchool of Nursing, Johns Hopkins University, Baltimore, Md., USA, and cDepartment of Animal Physiology, University of Bayreuth, Bayreuth, Germany
                54276 Neuroimmunomodulation 2000;8:154–164
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 1, References: 76, Pages: 11
                Original Paper


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