Identification of nicotinic acetylcholine receptors on lymphocytes in the periphery as well as thymus in mice

Toyabe, Shin-ichi; Iiai, Tsuneo; Fukuda, Mitsuhiro; Kawamura, Tatsuyuki; Suzuki, Susumu; Uchiyama, Makoto; Abo, Toru

doi:10.1046/j.1365-2567.1997.00323.x

Cited by 73 publications

(46 citation statements)

References 16 publications

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“…At this time, persons who experienced with hyperthermia showed granulocytosis and lymphocytopenia after the treatment. This might be due to the fact that overexposure of hyperthermia induced stressassociated sympathetic nerve activation and that granulocytes bear surface adrenergic receptors but lymphocytes bear surface cholinergic receptors (13,15). A similar response was also reported in animal studies (16).…”

supporting

confidence: 72%

Alkalization of blood pH is responsible for survival of cancer patients by mild hyperthermia

Ohishi

Nukuzuma

Seki³

et al. 2009

Biomed. Res.

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The effect of mild hyperthermia on venous blood pH was examined in 6 cancer patients. Mild hyperthermia was induced by continuation of a rectal temperature of 39.5°C for 30 min. All 6 patients were diagnosed as suffering from advanced cancer with or without surgery and chemotherapy pretreatments. In Cases 1 to 5, but not Case 6, venous blood pH was alkalized up to pH 7.7 by this mild hyperthermia and the effect was reproduced depending on the application of hyperthermia. At this time, alkalized pH was accompanied by increased PO 2 and decreased PCO 2 in the blood. These patients showed good physical conditions and improved clinical data. On the other hand, hyperthermia could not be continued in Case 6 due to his worsened physical condition. The present data suggest that mild hyperthermia is a useful method to improve circulation failure, physical condition and clinical data.Many cancer patients are suffering from hypothermia and circulation failure (8,11,12,18) due to vessel constriction induced by sympathetic nerve activation (1, 19). As a result, immunosuppression is often accompanied with these patients, showing lymphocytopenia. Restoration from this circulation failure seems to be important for the treatment of cancer. In this regard, there have been many trials of hyperthermia for the treatment of malignancy (6,9,17,20). Hyperthermia indeed ameliorates not only immune functions but also other physical conditions. In the course of these studies, we have noticed that hyperthermia (i.e., > 40°C) sometimes induced rather immunosuppression as a thermal stress (14). At this time, persons who experienced with hyperthermia showed granulocytosis and lymphocytopenia after the treatment. This might be due to the fact that overexposure of hyperthermia induced stressassociated sympathetic nerve activation and that granulocytes bear surface adrenergic receptors but lymphocytes bear surface cholinergic receptors (13,15). A similar response was also reported in animal studies (16). Dogs and cats which experienced with severe hyperthermia showed immunosuppression, showing granulocytosis and lymphocytopenia.In an earlier study, we showed that hyperthermia at the level up to 39.5°C (rectal temperature) for 30 min did not induce granulocytosis but rather induced immunopotentiation (14). In the present study, we applied this condition of hyperthermia for 6 cancer patients. As shown previously and in this study, an appropriate condition of hyperthermia is well correlated with the alkalization of blood pH with increased PO 2 and decreased PCO 2 after the application of hyperthermia. MATERIAL AND METHODS Subjects. Diagnosis of all cancer patients, including

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supporting

confidence: 72%

Alkalization of blood pH is responsible for survival of cancer patients by mild hyperthermia

Ohishi

Nukuzuma

Seki³

et al. 2009

Biomed. Res.

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“…It is possible that acetylcholine released by the vagus nerve acts on ␣7 expressed in the ganglia of the celiacsuperior mesenteric plexus to modulate splenic nerve function. But it is also clear that acetylcholine down-regulates cytokine release by splenic macrophages, and this effect requires the ␣7 subunit of the nicotinic acetylcholine receptor (12,44). Furthermore, the spleen contains and secretes acetylcholine, which may be released by stimulation of the splenic nerve (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

Rosas-Ballina¹,

Ochani²,

Parrish³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

609

569

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The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit ␣7, a mechanism termed ''the cholinergic antiinflammatory pathway.'' Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of ␣7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiacsuperior mesenteric plexus, and projecting in the splenic nerve.brain ͉ cytokine ͉ innate ͉ spleen ͉ vagus T he autonomic nervous system is divided into two major branches based on anatomy and function. These divisions, sympathetic and parasympathetic, control organ function through a set of two serially connected neurons, the first of which is located in the CNS and the second in the peripheral ganglia. Typically, parasympathetic neurons originate in the brainstem medulla and sacral portion of the spinal cord, and the ganglia are located close to or within the innervated organ. Sympathetic neurons originate in the thoracic and lumbar portion of the spinal cord, and the ganglia are situated close to the spinal cord.

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“…10,14 The a7nAChR can be considered to be a peripheral 'immune' component of the cholinergic anti-inflammatory pathway. 18,19 Molecular mechanisms supporting these anti-inflammatory effects include nuclear factor kappa B pathway inhibition, 20 activation of Janus activated kinase --signal transducer and activator of transcription 21 and the consequent inhibition of TNFa production. 22 A functional role of nicotinic acetylcholine receptors (nAChRs) has already been demonstrated in rat adipocytes.…”

Section: Discussionmentioning

confidence: 99%

The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss

et al. 2012

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BACKGROUND: It is known that cholinergic anti-inflammatory reflex regulates inflammation in peripheral tissues. Nicotinic acetylcholine receptors (nAChRs) are mediators of this anti-inflammatory pathway and also non-neuronal cells express functional nAChrs. A role for a7-subtype acetylcholine cholinergic receptor (a7nAChR) in insulin sensitivity improvement has already been shown in rodents both in vivo and in vitro. However, no data are available on a7nAChR expression in human adipocytes. OBJECTIVE: To investigate the expression and protein content of a7nAChR in human subcutaneous adipose tissue (SAT) and in isolated mature adipocytes. DESIGN: A total of 39 SAT biopsy specimens obtained from obese and normal-weight subjects were used to assess a7nAChR messenger RNA levels and to stimulate a7nAChR with a specific agonist and antagonist in vitro. Additional SATs from eight non-diabetic obese subjects were also studied, before and after a 3-month lifestyle intervention. RESULTS: a7nAChR expression was significantly lower in the SAT of obese subjects compared with that of normal-weight subjects. In mature adipocytes isolated from morbidly obese subjects (body mass index440 kg m À2 ), a7nAChR expression was 75% lower compared with adipocytes from normal-weight subjects. In adipocytes of obese subjects, a7nAChR was downregulated also at protein level. In eight non-diabetic obese subjects, a lifestyle intervention (3 months of diet and physical activity) induced a significant weight loss and an increase in a7nAChR SAT expression. In vitro stimulation of adipocytes with the specific a7nAChR agonist PNU282987 induced a significant anti-inflammatory effect. Furthermore, a similar downregulation of the inflammatory profile, associated with a significant increase in a7nAChR protein level, was observed after genistein stimulation. CONCLUSIONS: These results provide evidence that a7nAChR expression levels are significantly decreased in obese subjects, and that this receptor modulates inflammatory gene expression in human adipocytes. The upregulation of a7nAChR by genistein stimulation opens new insights for the management of low-grade inflammation linked to human obesity.

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Identification of nicotinic acetylcholine receptors on lymphocytes in the periphery as well as thymus in mice

Cited by 73 publications

References 16 publications

Alkalization of blood pH is responsible for survival of cancer patients by mild hyperthermia

Alkalization of blood pH is responsible for survival of cancer patients by mild hyperthermia

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss

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