MinireviewThe lymphocytic cholinergic system and its contribution to the regulation of immune activity
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.
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