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

Abstract

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.

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

“…30 The factors that can affect both the repertoire and the ligandbinding affinities of cholinergic receptors include the dose and duration of exposure to an agonist, antigen stimulation, cytokine milieu and a large variety of other non-immunological and immunological stimulations. [2][3][4]10,22,[31][32][33][34][35][36][37][38] This helps in explaining the discrepancy of our in vitro findings with the previous report that nicotine treatment of mice with experimental autoimmune encephalomyelitis fosters a shift from Th1 toward Th2 or Th3 responses. 38 In that study, however, the reduction in secreted IFN-g was most marked in CD8 compared with CD4 cells.…”

“…[3][4][5][6] It has been demonstrated that the immunological activation of lymphocytes evokes cholinergic signal transmission between T cells and target cells by enhancing synthesis and release of ACh and modifying the expression of ACh receptors (reviewed in ref. 2). T cells produce more ACh than B cells, and CD4 cells more than CD8 cells.…”

“…1,2 Its role in the development of T cells and generation of specific T-cell repertoire is being intensively studied. Human lymphocytes express cholinergic receptors and enzymes that constitute an independent non-neuronal cholinergic system, or ACh axis, that can either upregulate or downregulate the immune response.…”

“…9 Upon interaction with antigen-presenting cells via T-cell receptor (TCR)/ CD3, T cells show enhanced synthesis and release of ACh. 2 ACh and related compounds elicit biological effects through binding to the nicotinic and muscarinic classes of ACh receptors, nAChRs and mAChRs. The reported effects vary a great deal, and sometimes are diametrically opposite (reviewed in ref.…”

The cholinergic system in rat testis is of non-neuronal origin

“…ACh can stimulate five different G-protein-coupled muscarinic receptor subtypes (CHRMs, also known as mAChR ;Nathanson 2008) and an unknown variety of ionotropic nicotinic ACh receptors (CHRN; also known as nAChR) with subtype-specific arrangements of nine a-and four b-subunits in mammals (Albuquerque et al 2009). It is now known that the cholinergic system, traditionally associated with neurotransmission, is not restricted to neurons but plays an important role in the structure and function of non-neuronal tissues such as epithelia and the immune system (Fujii et al 2008, Kummer et al 2008, Wessler & Kirkpatrick 2008. For example, in epithelia, CHRNs are involved both in maintaining the integrity of the epithelial layer and in the development of neoplastic changes (Grando et al 2003, Grozio et al 2007, Paleari et al 2009).…”