Basic and clinical aspects of non-neuronal acetylcholine: expression of an independent, non-neuronal cholinergic system in lymphocytes and its clinical significance in immunotherapy.
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 nAChR-mediated 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 cholesterol-lowering 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 alpha7 and alpha5 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 alpha7 nAChR-mediated pathways. In fact, studies of humoral antibody production in M(1)/M(5) mAChR-deficient and alpha7 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.
Fujii
Takeshi
T
Department of Pharmacology, Kyoritsu College of Pharmacy, Minato-ku, Tokyo, Japan. tfujii@dwc.doshisha.ac.jp
Takada-Takatori
Yuki
Y
Kawashima
Koichiro
K
D000109:Acetylcholine / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000954:Antigens, Surface / Q000276:immunology; D006801:Humans; D007154:Immune System Diseases / Q000276:immunology*; D007155:Immunologic Factors / Q000494:pharmacology; D007167:Immunotherapy; D008214:Lymphocytes / Q000276:immunology*; D009474:Neurons; D019821:Simvastatin / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D007155:Immunologic Factors; D019821:Simvastatin; D000109:Acetylcholine