Elsevier

Life Sciences

Volume 74, Issue 6, 26 December 2003, Pages 675-696
Life Sciences

Minireview
The lymphocytic cholinergic system and its contribution to the regulation of immune activity

https://doi.org/10.1016/j.lfs.2003.09.037Get rights and content

Abstract

Lymphocytes express most of the cholinergic components found in the nervous system, including acetylcholine (ACh), choline acetyltransferase (ChAT), high affinity choline transporter, muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively), and acetylcholinesterase. Stimulation of T and B cells with ACh or another mAChR agonist elicits intracellular Ca2+ signaling, up-regulation of c-fos expression, increased nitric oxide synthesis and IL-2-induced signal transduction, probably via M3 and M5 mAChR-mediated pathways. Acute stimulation of nAChRs with ACh or nicotine causes rapid and transient Ca2+ signaling in T and B cells, probably via α7 nAChR subunit-mediated pathways. Chronic nicotine stimulation, by contrast, down-regulates nAChR expression and suppresses T cell activity. Activation of T cells with phytohemagglutinin or antibodies against cell surface molecules enhances lymphocytic cholinergic transmission by activating expression of ChAT and M5 mAChR, which is suggestive of local cholinergic regulation of immune system activity. This idea is supported by the facts that lymphocytic cholinergic activity reflects well the changes in immune system function seen in animal models of immune deficiency and immune acceleration. Collectively, these data provide a compelling picture in which lymphocytes constitute a cholinergic system that is independent of cholinergic nerves, and which is involved in the regulation of immune function.

Introduction

Acetylcholine (ACh) is generally known as a neurotransmitter in the central and peripheral nervous systems; as such, most current knowledge on the synthesis, storage, metabolism and actions of ACh is derived from studies of the nervous system. It is well established that ACh is synthesized from choline taken up by the high affinity choline transporter (CHT1) (Okuda et al., 2000) and acetylCoA by choline acetyltransferase (ChAT, EC 2.3.1.6) in the cytosol of central cholinergic nerve terminals and by ChAT and, to a lesser extent, carnitine acetyltransferase (EC 2.3.1.7) in the periphery Tuček, 1982, Tuček, 1988. The synthesized ACh is then transported into synaptic vesicles by vesicular ACh transporter (VAChT) and is stored there until released by exocytosis mediated by a rise in the intracellular free Ca2+ concentration ([Ca2+]i) (Usdin et al., 1995). Once released, ACh acts on either muscarinic or nicotinic ACh receptors (mAChR and nAChR, respectively), depending on the target innervated. Expression of various subtypes of both mAChRs and nAChRs, and their specific functions, is now under extensive investigation in both the central and peripheral nervous systems. The action of ACh is terminated by its degradation into choline and acetate by acetylcholinesterase (AChE, EC 3.1.1.7) at neuromuscular and neuroeffector junctions, and by butyrylcholinesterase, also known as cholinesterase (ChE), in plasma, liver and neuronal elements.

On the basis of the findings summarized above, we conclude that an assemblage of the following components constitutes a cholinergic system: ACh, ChAT, CHT1, VAChT, mAChRs and nAChRs, and AChE. Moreover, it should also be kept in mind that AChE, mAChRs and nAChRs are expressed not only in cholinergic nerves, but also in other nerves and in non-neural tissues that may or may not be innervated by cholinergic nerves (e.g., Bellinger et al., 1993). In this minireview, we will discuss 1) expression of non-neuronal ACh; 2) expression of cholinergic components in lymphocytes; 3) the role of ACh in the regulation of lymphocyte activity; 4) regulation of lymphocytic cholinergic activity by immunological stimulation; and 5) involvement of the lymphocytic cholinergic system in the regulation of immune function.

Section snippets

Expression of non-neuronal ACh

Evidence suggests the cholinergic system developed about 2.5 billion years prior to the emergence of animals with nervous systems (see a review by Grando et al., 2003). In fact, using a specific radioimmunoassay (RIA) (Kawashima et al., 1980), Horiuchi et al. (2003) confirmed the expression of ACh and ACh-synthesizing activity in bacteria, fungi, and a variety of other plants and animals. One notable example is the upper portion of the bamboo shoot, which grows as much as 10–20 cm per day and

Expression of cholinergic components in lymphocytes

mAChRs, nAChRs and AChE activity have all been detected in lymphocytes using ligand binding assays and immunohistochemical and immunocytochemical analyses. In addition, agonist stimulation of lymphocytes in vitro induces an array of functional and biochemical effects Kawashima et al., 1998, Kawashima and Fujii, 2000, Maslinski, 1989. On that basis, it was widely believed that the parasympathetic nervous system participated in various neuro-immune interactions Maslinski, 1989, Rinner and

Role of ACh in the regulation of lymphocyte activity

In vitro, ACh and other mAChR and nAChR agonists enhance lymphocyte cytotoxicity, increase their content of cGMP and inositol-1,4,5-triphosphate (IP3), and modulate DNA synthesis and cell proliferation (see reviews by Kawashima and Fujii, 2000, Maslinski, 1989), all of which support the idea that the lymphocytic cholinergic system is involved in the regulation of immune function via AChRs coupled to phospholipase-C (PLC). The mechanisms involved in mAChR- and nAChR-associated functional and

Regulation of lymphocytic cholinergic activity by immunological stimulation

Stimulation of T or B cells with their respective activators via cell surface molecules (T cell receptor (TCR)/CD3 molecule complexes, CD11a or surface immunoglobulin on B cells) causes up-regulation of ChAT and M5 mAChR expression Fujii et al., 1996, Fujii et al., 1998, Fujii et al., 2002, Fujii et al., 2003a, Fujii et al., 2003b, Rinner et al., 1998. Immunological activation of lymphocytes thus appears to enhance local cholinergic signal transmission between T cells and their targets, which

Involvement of the lymphocytic cholinergic system in the regulation of immune system function

Evidence suggests that changes in lymphocytic cholinergic activity are related to the immune dysfunction seen in the spontaneously hypertensive rat (SHR), an immune deficiency model (for review see Takeichi, 1995), and in the MRL/MpJ-lpr/lpr (MRL-lpr) mouse, an immune accelerated model Morse et al., 1982, Fossati et al., 1993.

Conclusions

It is now apparent that lymphocytes express most of the cholinergic components expressed in neurons and constitute an independent cholinergic system (Fig. 6). Upon interaction with antigen presenting cells via TCR/CD3 and CD4 or CD8, or with vascular endothelial cells or inflammatory cells via cell surface molecules, T cells show enhanced synthesis and release of ACh, which in turn acts on mAChRs and nAChRs on T and B cells or on other targets in the microenvironment. Stimulation of T and B

Acknowledgements

Supported in part by a Grant-in Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan (No. 14370037) and by a Grant from the Smoking Research Foundation.

References (98)

  • T. Fujii et al.

    Nicotine induces intracellular calcium signaling in T- and B-lymphocytes via neuronal-type nicotinic receptors dependently on extracellular calcium ion

  • T. Fujii et al.

    Effects of human antithymocyte globulin on acetylcholine synthesis, its release and choline acetyltransferase transcription in a human leukemic T-cell line

    Journal of Neuroimmunology

    (2002)
  • T. Fujii et al.

    Detection of the high-affinity choline transporter in the MOLT-3 human leukemic T-cell line

    Life Sciences

    (2003)
  • K. Fujimoto et al.

    Decreased acetylcholine content and choline acetyltransferase mRNA expression in circulating mononuclear leukocytes and lymphoid organs of the spontaneously hypertensive rat

    Life Sciences

    (2001)
  • Y. Geng et al.

    Effects of nicotine on the immune response. I. Chronic exposure to nicotine impairs antigen receptor-mediated signal transduction in lymphocytes

    Toxicology and Applied Pharmacology

    (1995)
  • S.A. Grando

    Biogical functions of keratinocyte cholinergic receptors

    Journal of Investigative Dermatology Symposium Proceeding

    (1997)
  • S.A. Grando et al.

    Editorial: The non-neuronal cholinergic system in humans

    Life Sciences

    (2003)
  • E. Hellström-Lindahl et al.

    Muscarinic receptor subtypes in subpopulations of human blood mononuclear cells as analyzed by RT-PCR technique

    Journal of Neuroimmunology

    (1996)
  • C. Hiemke et al.

    Expression of alpha subunit genes of nicotinic acetylcholine receptors in human lymphocytes

    Neuroscience Letters

    (1996)
  • Y. Horiuchi et al.

    Evolutional study on acetylcholine expression

    Life Sciences

    (2003)
  • C. Ikeda et al.

    Phorbol ester stimulates acetylcholine synthesis in cultured endothelial cells isolated from porcine cerebral microvessels

    Brain Research

    (1994)
  • Y. Kamimura et al.

    Nitric oxide (NO) synthase mRNA expression and NO production via muscarinic acetylcholine receptor-mediated pathways in the CEM, human leukemic T-cell line

    Life Sciences

    (2003)
  • K. Kawashima et al.

    Radioimmunoassay for acetylcholine in the rat brain

    Journal of Pharmacological Methods

    (1980)
  • K. Kawashima et al.

    Synthesis and release of acetylcholine by cultured bovine arterial endothelial cells

    Neuroscience Letters

    (1990)
  • K. Kawashima et al.

    Acetylcholine synthesis and muscarinic receptor subtype mRNA expression in T-lymphocytes

    Life Sciences

    (1998)
  • K. Kawashima et al.

    Extraneuronal cholinergic system in lymphocytes

    Pharmacology and Therapeutics

    (2000)
  • C.J. Kirkpatrick et al.

    The non-neuronal cholinergic system in the endothelium: evidence and possible pathological significance

    Japanese Journal of Pharmacology

    (2001)
  • Y.-P. Kuo et al.

    Differential expression of nicotinic acetylcholine receptor subunits in fetal and neonatal mouse thymus

    Journal of Neuroimmunology

    (2002)
  • L.R. Lustig et al.

    Molecular cloning and mapping of the human nicotinic acetylcholine receptor α10 (CHRNA10)

    Genomics

    (2001)
  • W. Maslinski

    Cholinergic receptors of lymphocytes

    Brain Behaviour and Immunology

    (1989)
  • M. Mihovilovic et al.

    Thymic epithelial cell line expresses transcripts encoding α-3, α-5 and β-4 subunits of acetylcholine receptors, responds to cholinergic agents and expresses choline acetyl transferase. An in vitro system to investigate thymic cholinergic mechanisms

    Journal of Neuroimmunology

    (2001)
  • H. Misawa et al.

    Human choline acetyltransferase mRNAs with different 5′-region produce a 69-kDa major translation product

    Molecular Brain Research

    (1997)
  • J. Nomura et al.

    The presence and function of muscarinic receptors in human T cells: The involvement in IL-2 and IL-2 receptor system

    Life Sciences

    (2003)
  • H. Ogawa et al.

    Expression of multiple mRNA species for choline acetyltransferase in human T-lymphocytes

    Life Sciences

    (2003)
  • Y. Okuma et al.

    Roles of muscarinic acetylcholine receptors in interleukin-2 synthesis in lymphocytes

    Japanese Journal of Pharmacology

    (2001)
  • A. Ricci et al.

    Expression of peripheral blood lymphocytes muscarinic cholinergic receptor subtypes in airway hyperresponsiveness

    Journal of Neuroimmunology

    (2002)
  • I. Rinner et al.

    The parasympathetic nervous system takes part in the immuno-neuroendocrine dialogue

    Journal of Neuroimmunology

    (1991)
  • I. Rinner et al.

    Rat lymphocytes produce and secrete acetylcholine in dependence of differentiation and activation

    Journal of Neuroimmunology

    (1998)
  • N. Sakuragawa et al.

    Non-neuronal neurotransmitter and neurotrophic factors in amniotic epithelial cells: expression and function in humans and monkey

    Japanese Journal of Pharmacology

    (2001)
  • B.V. Sastry

    Human placental cholinergic system

    Biochemical Pharmacology

    (1997)
  • K.Z. Sato et al.

    Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines

    Neuroscience Letters

    (1999)
  • S.P. Singh et al.

    Acute and chronic nicotine exposures modulate the immune system through different pathways

    Toxicology and Applied Pharmacology

    (2000)
  • S.K. Tayebati et al.

    Immunochemical and immunocytochemical characterization of cholinergic markers in human peripheral blood lymphocytes

    Journal of Neuroimmunology

    (2002)
  • T.B. Usdin et al.

    Molecular biology of the vesicular ACh transporter

    Trends in Neurosciences

    (1995)
  • Y. Villiger et al.

    Expression of an α7 duplicate nicotinic acetylcholine receptor-related protein in human leukocytes

    Journal of Neuroimmunology

    (2002)
  • I. Wessler et al.

    Non-neuronal acetylcholine, a locally acting molecule widely distributed in biological system: expression and function in humans

    Pharmacology and Therapeutics

    (1998)
  • I. Wessler et al.

    The biological role of non-neuronal acetylcholine in plants and humans

    Japanese Journal of Pharmacology

    (2001)
  • J.M. Williams et al.

    Sympathetic innervation of murine thymus and spleen: evidence for a functional link between the nervous and immune system

    Brain Research Bulletin

    (1981)
  • T. Ando et al.

    Expression of three acetylcholinesterase mRNAs in human lymphocytes

    Japanese Journal of Pharmacology

    (1999)
  • Cited by (272)

    View all citing articles on Scopus
    View full text