Table 1.
Effect of ChAT activators and inhibitors on the immune system.
| Molecules | Cholinergic effects | Effect of immune status | Experimental model |
|---|---|---|---|
| Estradiol | Increases ChAT activity in the forebrain (32, 33). | CD4+ T cells, B cells, and macrophages express estrogen receptors (34). Regulates innate immunity, antigen presentation, and adaptive immune response and has a protective anti-inflammatory effect (35). | 1. Ovariectomized RA mice (36). 2. Cancer model (37) 3. Autoimmune disease (38) |
| Trimethyltin (TMT) | TMT increases ChAT activity in the dentate gyrus (39). | TMT treatment causes atrophy of the thymus, spleen, and lymph nodes. Show reduced antibody levels, lymphocyte proliferation, NK cell function, and peritoneal macrophages’ phagocytic activity (40, 41). Induce microglial/astroglial activation (42). | 1.TMT-induced neurotoxic and seizure model (43). 2. Autophagy-induced Alzheimer and epilepsy (44) |
| A23187 | Affect calcium ionophore and increases ChAT expression in leukemic T cells. | A23187 induces the expression of IL-2 receptors in purified T cells (45). It stimulates the proliferation of allogeneic T cells and increases DC-stimulated cytotoxic T lymphocytes (46). A23187 treatment in macrophages causes leukotriene C4 release and enhanced macrophage anti-tumor activity (47). | |
| Anti-thymocyte globulin (ATG)-Fresenius | Upregulate ChAT expression mediated by CD11a and ACh release through transient increases in intracellular Ca2+ (48). | ATG induced a semi-mature phenotype DC with a tolerogenic phenotype that actively suppressed the T cell proliferation (49). Negatively influence B-cell immune reconstitution and deplete cytotoxic T cells (50). | Solid-organ transplantation and allogeneic stem cell transplantation in human (51). |
| Dibutyryl cAMP | PKA activator upregulates ChAT mRNA expression and ChAT activity and ACh production in the human leukemic cell (52). Dibutyryl cAMP treatment on adipocytes induced Chrna2 expression that controls whole-body metabolism (53). |
Dibutyryl-cAMP induces the endogenous production of cAMP and mimics the inhibitory effect of epinephrin on cytotoxic T lymphocytes (54). Cyclic AMP suppress the production of IL-2 in T cells but stimulate antigen-specific and polyclonal antibody production in B cells (55). | – |
| Phorbol 12-myristate 13-acetate (PMA) | Nonspecific PKC activator. It promotes the expression of both M3/M5 mAChR and ChAT mRNA in endothelial cells and spinal cord neurons. Thus, activating cholinergic signaling (56, 57). |
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| Phytohemagglutinin (PHA) | Antigen-induced T cell activation via TCR/CD3ε complexes enhances upregulation of ChAT and M5 mAChR expression (58). | PHA-activated lymphocytes respond to cholinergic stimulation with an increase in their free cytoplasmic Ca2+ levels. | |
| Naphthyl-vinyl-pyridine derivatives (NVP) | NVP’s method of ACh antagonism involves inhibiting the enzyme. | LPS challenged Splenic Lymphocyte-derived ACh was prevented by cotreatment with NVP (59). | |
| α-NETA | α-NETA exhibits a potent inhibitory activity of ChAT | α-NETA treatment significantly delays the onset of EAE. It antagonizes Chemokine-like receptor-1 (CMKLR1) and inhibits β-arrestin-2 cell migration (60). | |
| Bromoacetylcholine and Bromoacetylcarnitine | Inhibits ChAT and carnitine acetyltransferase (CarAT) activity to synthesize ACh | Synthesis of ACh was reduced by 50 percent in various leukemic T cell lines upon inhibition of ACh synthesizing enzymes (61). | |
| FK-506 (tacrolimus) | Reduces PHA-induced expression of ChAT mRNA and ACh synthesis through the calcineurin-mediated pathway | Treatment of MG (62). |