Localization and synthesis of acetylcholine in human leukemic T cell lines

Fujii, Takeshi; Tsuchiya, Teizo; Yamada, Shin; Fujimoto, Kazuko; Suzuki, Takeshi; Kimura, Tadashi; Kawashima, Koichiro

doi:10.1002/(sici)1097-4547(19960401)44:1<66::aid-jnr9>3.0.co;2-g

Cited by 101 publications

(58 citation statements)

References 38 publications

(38 reference statements)

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“…Phytohemagglutinin (PHA) activates T cells by binding to the T cell receptor (TCR) / CD3 molecule complex, which leads to activation of the phospholipase C (PLC)-inositol-1,4,5-trisphosphate system and, in turn, the protein kinase C (PKC) and / or mitogen-activated protein kinase (MAPK) cascades. Stimulation of MOLT-3 human leukemic T cells using PHA increases both intracellular ACh content and its release (15), and all of these effects of PHA, including the up-regulation of ChAT transcription, have been confirmed in human MNLs (5) and rat T cells (8). The increases in cellular ACh content and release exhibited by activated T-lymphocytes thus appear to be mediated, at least in part, by increased expression of ChAT.…”

Section: Factors That Modulate Lymphocytic Cholinergic Activitymentioning

confidence: 85%

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of an Independent, Non-neuronal Cholinergic System in Lymphocytes and Its Clinical Significance in Immunotherapy

Fujii

Takada‐Takatori

Kawashima³

2008

J Pharmacol Sci

106

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Abstract. Lymphocytes possess all the components required to constitute an independent, non-neuronal cholinergic system. These include acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). ACh modifies T and B cell function via both mAChR-and nAChRmediated pathways. Stimulation of lymphocytes with the T cell activator phytohemagglutinin, protein kinase C activator phorbol ester, or cell surface molecules enhances the synthesis and release of ACh and up-regulates ChAT and / or M 5 mAChR gene expression. Furthermore, animal models of immune disorders exhibit abnormal lymphocytic cholinergic activity. The cholesterollowering drug simvastatin attenuates the lymphocytic cholinergic activity of T cells by inhibiting LFA-1 signaling in a manner independent of its cholesterol-lowering activity. This suggests that simvastatin exerts its immunosuppressive effects in part by modifying lymphocytic cholinergic activity. Nicotine, an active ingredient of tobacco, ameliorates ulcerative colitis but exacerbates Crohn's disease. Expression of mRNAs encoding the nAChR α7 and α5 subunits are significantly diminished in peripheral mononuclear leukocytes from smokers, as compared with those from nonsmokers. In addition, long-term exposure of lymphocytes to nicotine reduces intracellular Ca 2+ signaling via α7 nAChR-mediated pathways. In fact, studies of humoral antibody production in M 1 / M 5 mAChR-deficient and α7 nAChR-deficient animals revealed the role of lymphocytic cholinergic activity in the regulation of immune function. These results provide clues to understanding the mechanisms underlying immune system regulation and could serve as the basis for the development of new immunomodulatory drugs.

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Section: Factors That Modulate Lymphocytic Cholinergic Activitymentioning

confidence: 85%

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of an Independent, Non-neuronal Cholinergic System in Lymphocytes and Its Clinical Significance in Immunotherapy

Fujii

Takada‐Takatori

Kawashima³

2008

J Pharmacol Sci

106

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“…Kawashima and Wessler [30,31] speculated that non-neuronal and non-central cells synthesize ACh. Our recent study has demonstrated for the first time that cardiomyocytes also possess the intracellular ACh synthesis system, which is transcriptionally activated in a positive feedback manner, and donepezil also elevates ACh level in cardiomyocytes, which was partly independent of muscarinic receptors [29].…”

Section: Discussionmentioning

confidence: 99%

Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model

Kakinuma

Furihata²,

Akiyama

et al. 2010

Journal of Molecular and Cellular Cardiology

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“…On the basis of the aforementioned findings, attempts were made to verify the origin of blood ACh by measuring the ACh content and ChAT activity in human leukemic cell lines serving as models of lymphocytes (Table 2) (11,12). Significant amounts of ACh were found in T-cell lines, along with corresponding ChAT activity, whereas little ACh or ChAT activity were observed in the remaining lines.…”

Section: Ach Synthesis By Chat In T-lymphocytesmentioning

confidence: 99%

“…Stimulation of MOLT-3 cells and rat T-cells with phytohemagglutinin (PHA) increased both the intracellular ACh content of the cells and its subsequent release (11,16). Moreover, PHA induced expression of ChAT mRNA and potentiated ChAT activity in human MNLs, indicating that activation of T-lymphocytes upregulates ACh synthesis largely via induction of ChAT expression (15,16).…”

Section: Modulation Of the Lymphoid Cholinergic Systemmentioning

confidence: 99%

The Non-neuronal Cholinergic System

Fujii¹,

Kawashima²

2001

Japanese Journal of Pharmacology

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ABSTRACT-Acetylcholine (ACh) is a well characterized neurotransmitter occurring throughout the animal kingdom. In addition, both muscarinic and nicotinic ACh receptors have been identified on lymphocytes of various origin, and their stimulation by muscarinic or nicotinic agonists elicits a variety of functional and biochemical effects. It was thus initially postulated that the parasympathetic nervous system may play a role in modulating immune system function. However, ACh in the blood has now been localized to lymphocytes; indeed expression of choline acetyltransferase (ChAT), an ACh synthesizing enzyme, has been shown in human blood mononuclear leukocytes, human leukemic T-cell lines and rat lymphocytes. Stimulation of Tlymphocytes with phytohemagglutinin activates the lymphoid cholinergic system, as evidenced by increased synthesis and release of ACh and increased expression of mRNAs encoding ChAT and ACh receptors. The observation that M 3 muscarinic receptor stimulation by ACh and other agonists increases the intracellular free Ca 2 + concentration and upregulates c-fos gene expression strongly argues that ACh, synthesized and released from T-lymphocytes, acts as an autocrine and / or paracrine factor regulating immune function. These findings present a compelling picture in which immune function is, at least in part, under the control of an independent lymphoid cholinergic system.

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Localization and synthesis of acetylcholine in human leukemic T cell lines

Cited by 101 publications

References 38 publications

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of an Independent, Non-neuronal Cholinergic System in Lymphocytes and Its Clinical Significance in Immunotherapy

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of an Independent, Non-neuronal Cholinergic System in Lymphocytes and Its Clinical Significance in Immunotherapy

Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model

The Non-neuronal Cholinergic System

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