Structure and function of the nicotinic arm of acetylcholine regulatory axis in human leukemic T cells.
Although acetylcholine (ACh) is widely known as a neurotransmitter, it also functions as a local humoral factor translating environmental stimuli into alterations in T cell development and function. The cholinergic components present in neurons are expressed in T cells where they constitute an independent cholinergic system. Both non-immunologic and immunologic stimulations can alter expression and function of cholinergic elements in T cells. Recent studies have convincingly demonstrated regulation of immune system by auto/paracrine ACh, which provides a basis for development of new immunomodulatory therapies with nicotinic agonists. The purpose of our research is to integrate information about the structure and activity of the ACh regulatory axis with the phenotypic and functional alterations of T cells during their development and commitment. In this study, we used the Ach producing human leukemic T cell line CCRF-CEM (CEM) to investigate auto/paracrine mechanisms of T cell regulation through the nicotinic class of ACh receptors (nAChRs). The intact CEM expressed alpha3, alpha5, alpha6, alpha7, alpha 9, beta2 and beta4 nAChR subunits. Stimulation of CEM with 10 microg/ml of phytohemagglutinin (PHA) for 16 h upregulated expression of the alpha3, alpha5, alpha7, alpha9 and beta2 and downregulated that of alpha6 and beta4 subunits, indicating that TCR activation leads to overexpression of high Ca2+-permeable ACh-gated ion channels. Activation of alpha7- and alpha3 AChRs predominantly abrogated PHA-dependent upregulation of the pro-inflammatory cytokine TNF-alpha and IFN-gamma receptors, respectively, at the mRNA and protein levels. Signaling through alpha7 and alpha3 nAChRs also significantly (p<0.05) altered expression of the cell state regulators p21 and Bcl-2, respectively, suggesting that downregulation of inflammation via nAChRs includes effects on the T cell cycle progression and apoptosis. These findings indicate that constant stimulation of alpha7 and alpha3 nAChRs by endogenously released ACh controls T cell activation and that signaling downstream of distinct nAChR subtypes targets specific inflammatory and cell cycle genes. Learning the cholinergic pharmacology of inflammation should allow to regulate specific types of immune reactions by selectively activating or blocking the types of nAChRs expressed by the immune cells mediating specific immune reactions.
Chernyavsky
A I
AI
Center for Immunology and Departments of Dermatology and Biological Chemistry, University of California, Irvine, CA, USA.
Arredondo
J
J
Galitovskiy
V
V
Qian
J
J
Grando
S A
SA
D000109:Acetylcholine / Q000378:metabolism*; D019898:Autocrine Communication; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D015458:Leukemia, T-Cell / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology; D019899:Paracrine Communication; D010835:Phytohemagglutinins / Q000494:pharmacology; D021122:Protein Subunits; D017471:Receptors, Interferon / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000096743:Interferon gamma Receptor
D000109:Acetylcholine; D008934:Mitogens; D010835:Phytohemagglutinins; D021122:Protein Subunits; D017471:Receptors, Interferon; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000096743:Interferon gamma Receptor; C579167:Chrna7 protein, human