Immobilization increases norepinephrine release and reduces NK cytotoxicity in spleen of conscious rat

Shimizu, Nobuaki; Kaizuka, Yasuo; Hori, Tatsuya; Nakane, Hideyuki

doi:10.1152/ajpregu.1996.271.3.r537

Cited by 18 publications

(17 citation statements)

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“…Specifically, immune organs such as spleen, thymus, and lymph nodes are innervated by the sympathetic nervous system (SNS) [24]; NK cells express adrenergic receptors [25,26] and their activity is modulated in vitro by adrenergic agents [27][28][29]. Electrical stimulation of the splenic nerve [30], chemical or surgical sympathectomy [31][32][33], and blockade of sympathetic activity [28,[34][35][36][37][38] have all been shown to alter NKA. Similar manipulations have been shown to affect tumor development as well [39][40][41].…”

Section: Introductionmentioning

confidence: 99%

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

Ben‐Eliyahu

Shakhar

Page

et al. 2000

Neuroimmunomodulation

205

114

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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 β₁- and β₂-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 β₁- (atenolol, 1–6 mg/kg) and a selective β₂-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 β₁- and β₂-adrenoceptors, suppresses NKA and consequently compromises resistance to NK-sensitive metastasis.

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Section: Introductionmentioning

confidence: 99%

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

Ben‐Eliyahu

Shakhar

Page

et al. 2000

Neuroimmunomodulation

205

114

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“…Substances that are more likely to be involved belong to 2 classes: those that cause the redistribution of NK cells, such as corticosteroids 40 and catecholamines, 18 and those secreted locally in certain immune compartments, as is the case with norepinephrine secretion by sympathetic fibers in the spleen. 19,20 When in vivo NK-dependent tumor clearance was assessed within a single lighting phase, substantial diurnal changes were observed. Perhaps not surprisingly, these fluctuations were not reflected in a longer term index of metastatic development.…”

Section: Discussionmentioning

confidence: 99%

“…17 When NKCC is assessed not per NK cell but in a heterogeneous cell population (such as PBMCs), conditions that affect the reallocation of NK cells between organs can yield paradoxic results, raising NKCC in 1 compartment and lowering it in another. 18 Additionally, innervation of immune compartments, such as the spleen, may result in organ-specific modulation of NKCC, 19,20 and tissue-specific cell populations that interact with NK cells may affect them differentially. 21 To understand better the biologic and clinical significance of circadian changes in NKCC, it is important to complement the in vitro assay with a more natural in vivo index of NKCC.…”

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confidence: 99%

Diurnal changes in lung tumor clearance and their relation to NK cell cytotoxicity in the blood and spleen

2001

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Natural killer cell cytotoxicity (NKCC) was reported to manifest a circadian rhythm, peaking during wakefulness in both human blood and rat spleen. Using F344 rats, we investigated whether such fluctuations (i) reflect changes in NK cell numbers or in cytotoxicity per cell; (ii) coincide in the blood and spleen; (iii) correspond with clearance of NK-sensitive tumor cells from the lungs and (iv) influence formation of lung metastases. Two rat groups were housed in opposite 12:12 hr lighting regimens. Two hours after the onset of light or dark, both groups were either sacrificed or intravenously inoculated with tumor cells to study the following indices: NKCC and NK cell numbers in the spleen (n ‫؍‬ 29) and blood (n ‫؍‬ 79), lung clearance of tumor cells (n ‫؍‬ 142) and lung metastasis (n ‫؍‬ 69). The tumor employed, MADB106, is an NK-sensitive mammary adenocarcinoma that metastasizes only to the lungs. The results indicated that, during the dark phase, splenic NKCC increased (37% higher lytic unit [LU] 50 ) mostly due to a 28.9% higher percentage of NK cells in the spleen. In contrast, blood NKCC decreased by 42.5% (LU 20 ) and this decline was independent of circulating NK cell numbers, which remained constant. Lung tumor clearance increased in the dark (up to 42% lower retention 9 hr after inoculation), but no corresponding changes in the number of metastases were observed 3 weeks later. We conclude that diurnal changes in rats' NKCC are organ-specific, involve changes in both cell distribution and activity and may affect short-term in vivo indices of NK tumoricidal activity. Natural killer (NK) cells, discovered 25 years ago, 1 are a subset of lymphocytes that spontaneously recognize and lyse virally infected and malignant cells. 2 In vivo, they are believed to play a substantial role in controlling the metastasis of several malignancies. This premise is based on the better prognosis associated with higher NK cell cytotoxicity (NKCC) in cancer patients 3 and is corroborated by several animal models that demonstrate a critical role for NK cells in controlling experimentally induced metastasis. 4,5 A number of immunologic indices, such as the production of several cytokines and the numbers and activity of various immune cells, show circadian fluctuations of appreciable magnitude, 6,7 but the in vivo ramifications of these fluctuations are largely unknown. A circadian rhythm of NKCC in humans has been documented by a substantial number of studies, most of which recorded increased NKCC in the blood during the day. 8 -11 Most of these studies used the standard NKCC assay, which measures NKCC per a fixed number of peripheral blood mononuclear cells (PBMCs). Because the percentage of NK cells within PBMCs also peaks during the day, 10,12,13 it is not clear how much of the rise in NKCC results from an increased proportion of NK cells within PBMCs and how much from changes in the cytotoxicity of individual NK cells.In rats, NKCC has been studied in the spleen. 14 -16 These studies located the maximal and minimal level...

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“…injections of ß-endorphin and CRF [49]. Immobilization, which is known to induce opioid-dependent analgesia for 80 min also increased the noradrenaline release in the spleen and reduced the splenic NK cytotoxicity [50]. Both the increased levels of splenic noradrenaline and the immunosuppression were almost abolished by splenic denervation.…”

Section: Hypothalamic Modulation Of the Activity Of Splenic Sympathetmentioning

confidence: 93%

Neuroimmunomodulatory Actions of Hypothalamic Interferon-α

Hori

Katafuchi

Take

et al. 1998

Neuroimmunomodulation

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Recent studies have revealed that the brain produces interferon-α (IFN-α) in response to noninflammatory as well as inflammatory stress and that it might have a role in normal physiology. When administered intracerebrally, IFN-α causes diverse effects including fever, anorexia, analgesia and changes in the central neuronal activities. These responses are inhibited by the opioid receptor antagonist naloxone. This is consistent with the reports suggesting that recombinant human (rh) IFN-α binds to opioid receptors in rodent brain membrane. We revealed that rhIFN-α altered the activity of thermosensitive neurons in the medial preoptic area (MPO) and glucose-responsive neurons in the ventromedial hypothalamus in an opioid-receptor-dependent way. As a stress which produces opioid-dependent analgesia is known to suppress the cytotoxicity of splenic natural killer cells, we investigated whether the administration of β-endorphin and rhIFN-α may induce a similar immunosuppression. We found that central, but not peripheral, injection of both compounds inhibited natural killer (NK) cytotoxicity. Further studies revealed that rhIFN-α decreased the activity of MPO neurons via opioid receptors and the altered activity of MPO neurons in turn resulted in the activation of corticotropin-releasing factor neurons, thereby suppressing NK cytotoxicity predominantly through activation of the splenic sympathetic nerve and β-receptor mechanisms in splenocytes. Thus, IFN-α may alter the brain activity to exert a feedback effect on the immune system. Further detailed whole-cell clamping analyses on neuronal mechanisms in rat brain tissue slices showed that the inhibitory effect of rhIFN-α on N-methyl-D-aspartate-induced membrane current responses of MPO neurons was mediated not only by opioid receptors but also by the local production of reactive oxygen intermediates, nitric oxide and prostanoids, possibly due to neuron-glial cell interaction.

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Immobilization increases norepinephrine release and reduces NK cytotoxicity in spleen of conscious rat

Cited by 18 publications

References 0 publications

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

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

Diurnal changes in lung tumor clearance and their relation to NK cell cytotoxicity in the blood and spleen

Neuroimmunomodulatory Actions of Hypothalamic Interferon-α

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