The Non-neuronal Cholinergic System of Human Skin

Abstract

In human skin both resident and transiently residing cells are part of the extra- or non-neuronal cholinergic system, creating a highly complex and interconnected cosmos in which acetylcholine (ACh) and choline are the natural ligands of nicotinic and muscarinic receptors with regulatory function in both physiology and pathophysiology. ACh is produced in keratinocytes, endothelial cells and most notably in immune competent cells invading the skin at sites of inflammation. The cholinergic system is involved in basic functions of the skin through autocrine, paracrine, and endocrine mechanisms, like keratinocyte proliferation, differentiation, adhesion and migration, epidermal barrier formation, pigment-, sweat- and sebum production, blood circulation, angiogenesis, and a variety of immune reactions. The pathophysiological consequences of this complex cholinergic “concert” are only beginning to be understood. The present review aims at providing insight into basic mechanisms of this highly complex system.

Keywords

acetylcholine - choline - endocrine - immune system - angiogenesis

References

• 1 Grando SA. Biological functions of keratinocyte cholinergic receptors.  J Invest Dermatol Symp Proc. 1997;  2 41-48
• 2 Zouboulis CC. Human skin: an independent peripheral endocrine organ.  Horm Res. 2000;  54 230-242
• 3 Schallreuter KU. Epidermal adrenergic signal transduction as part of the neuronal network in the human epidermis.  J Investig Dermatol Symp Proc. 1997;  2 37-40
• 4 Kurzen H, Schallreuter KU. Novel aspects in cutaneous biology of acetylcholine synthesis and acetylcholine receptors.  Exp Dermatol. 2004;  13 ((Suppl 4)) 27-30
• 5 Conti-Tronconi BM, McLane KE, Raftery MA, Grando SA, Protti MP. The nicotinic acetylcholine receptor: structure and autoimmune pathology.  Crit Rev Biochem Mol Biol. 1994;  29 69-123
• 6 Mark MR, Domino EF, Han SS, Ortiz A, Mathews BN, Tait SK. Effect of parasympathetic denervation on acetylcholine levels in the rat parotid gland. Is there an extraneuronal pool of acetylcholine?.  Life Sci. 1983;  33 1191-1197
• 7 Kawashima K, Oohata H, Suzuki T, Fujimoto K. Extraneuronal localization of acetylcholine and its release upon nicotine stimulation.  Neurosci Lett. 1989;  104 336-339
• 8 Horiuchi Y, Kimura R, Kato N, Fujii T, Seki M, Endo T, Kato T, Kawashima K. Evolutional study on acetylcholine expression.  Life Sci. 2003;  72 1745-1756
• 9 Kurzen H, Berger H, Jäger C, Hartschuh W, Näher H, Gratchev A, Goerdt S, Deichmann M. Phenotypical and molecular profiling of the extraneuronal cholinergic system of the skin.  J Invest Dermatol. 2004;  123 937-949
• 10 Wessler I, Kilbinger H, Bittinger F, Unger R, Kirkpatrick CJ. The non-neuronal cholinergic system in humans: expression, function and pathophysiology.  Life Sci. 2003;  72 2055-2061
• 11 van Koppen CJ, Kaiser B. Regulation of muscarinic acetylcholine receptor signaling.  Pharmacol Ther. 2003;  98 197-220
• 12 Millar N. Assembly and subunit diversity of nicotinic acetylcholine receptors.  Biochem Soc Trans. 2003;  31 869-874
• 13 Sgard F, Charpentier E, Bertrand S, Walker N, Caput D, Graham D, Bertrand D, Besnard F. A novel human nicotinic receptor subunit, α10, that confers functionality to the α9-subunit.  Mol Pharmacol. 2001;  61 150-159
• 14 Shi H, Wang H, Lu Y, Yang B, Wang Z. Choline modulates cardiac membrane repolarization by activating an M3 muscarinic receptor and its coupled K⁺ channel.  J Membr Biol. 1999;  169 55-64
• 15 Zwart R, Vijverberg HP. Potentiation and inhibition of neuronal nicotinic receptors by atropine: competitive and noncompetitive effects.  Mol Pharmacol. 1997;  52 886-895
• 16 Parker JC, Sarkar D, Quick MW, Lester RA. Interactions of atropine with heterologously expressed and native alpha 3 subunit-containing nicotinic acetylcholine receptors.  Br J Pharmacol. 2003;  138 801-810
• 17 Elgoyhen AB, Johnson D, Boulter J, Vetter DE, Heinemann S. α9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells.  Cell. 1994;  79 705-715
• 18 Grando SA, Zelickson BD, Kist DA, Weinshenker D, Bigliardi PL, Wendelschafer-Crabb G, Kennedy WR, Dahl MV. Keratinocyte muscarinic acetylcholine receptors: immunolocalization and partial characterization.  J Invest Dermatol. 1995;  104 95-100
• 19 Verbitsky M, Rothlin CV, Katz E, Elgoyhen AB. Mixed nicotinic-muscarinic properties of the alpha9 nicotinic cholinergic receptor.  Neuropharmacology. 2000;  39 2515-2524
• 20 Arredondo J, Nguyen VT, Chernyavsky AI, Bercovich D, Orr-Urtreger A, Kummer W, Lips K, Vetter DE, Grando SA. Central role of alpha7 nicotinic receptor in differentiation of the stratified squamous epithelium.  J Cell Biol. 2002;  159 325-336
• 21 Gharagozloo P, Lazareno S, Popham A, Birdsall NJ. Allosteric interactions of quaternary strychnine and brucine derivatives with muscarinic acetylcholine receptors.  J Med Chem. 1999;  42 438-445
• 22 Jakublik J, Backova L, El-Fakahany EE, Tucek S. Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors.  Mol Pharmacol. 1997;  52 172-179
• 23 Birdsall NJ, Farries T, Gharagozloo P, Kobayashi S, Lazareno S, Sugimoto M. Subtype-selective positive cooperative interactions between brucine analogs and acetylcholine at muscarinic receptors: functional studies.  Mol Pharmacol. 1999;  55 778-786
• 24 Chernyavsky AI, Arredondo J, Marubio LM, Grando SA. Differential regulation of keratinocyte chemokinesis and chemotaxis through distinct nicotinic receptor subtypes.  J Cell Sci. 2004;  117 5665-5679
• 25 Chernyavsky AI, Arredondo J, Karlsson E, Wessler I, Grando SA. The RAS/RAF-1/MEK1/ERK signaling pathway coupled to integrin expression mediates cholinergic regulation of keratinocyte directional migration.  J Biol Chem. 2005;  280 39220-39228
• 26 Blusztajn JK. Choline, a vital amine.  Science. 1998;  281 ((5378)) 794-795
• 27 Ilcol YO, Ozbek R, Hamurtekin E, Ulus IH. Choline status in newborns, infants, children, breast-feeding women, breast-fed infants and human breast milk.  J Nutr Biochem. 2005;  16 489-499
• 28 Mohs RC, Davis KL. Choline chloride effects on memory: correlation with the effects of physostigmine.  Psychiatry Res. 1980;  2 149-156
• 29 da Costa KA, Badea M, Fischer LM, Zeisel SH. Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts.  Am J Clin Nutr. 2004;  80 163-170
• 30 Holmes-McNary MQ, Baldwin Jr AS, Zeisel SH. Opposing regulation of choline deficiency-induced apoptosis by p53 and nuclear factor kappaB.  J Biol Chem. 2001;  276 41197-41204
• 31 Danne O, Mockel M, Lueders C, Mugge C, Zschunke GA, Lufft H, Muller C, Frei U. Prognostic implications of elevated whole blood choline levels in acute coronary syndromes.  Am J Cardiol. 2003;  91 1060-1067
• 32 Grando SA, Kist DA, Qi M, Dahl MV. Human keratinocytes synthesize, secrete, and degrade acetylcholine.  J Invest Dermatol. 1993;  101 32-36
• 33 Nguyen VT, Ndoye A, Hall LL, Zia S, Arredondo J, Chernyavsky AI, Kist DA, Zelickson BD, Lawry MA, Grando SA. Programmed cell death of keratinocytes culminates in apoptotic secretion of a humectant upon secretagogue action of acetylcholine.  J Cell Sci. 2001;  114 1189-1204
• 34 Lips KS, Pfeil U, Kummer W. Coexpression of α9 and α10 nicotinic acetylcholine receptor subunits in rat dorsal root ganglion neurons.  Neuroscience. 2002;  115 1-5
• 35 Elgoyhen AB, Vetter DE, Katz E, Rothlin CV, Heinemann SF, Boulter J. alpha10: a determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells.  Proc Natl Acad Sci USA. 2001;  98 3501-3506
• 36 Kurzen H, Berger H, Jager C, Hartschuh W, Maas-Szabowski N. Alpha 9 acetylcholine receptors are essential for epidermal differentiation.  Exp Dermatol. 2005;  14 155
• 37 Gordon PR, Gelman LK, Gilchrest BA. Demonstration of a choline requirement for optimal keratinocyte growth in a defined culture medium.  J Nutr. 1988;  118 1487-1494
• 38 Nguyen VT, Chernyavsky AI, Arredondo J. et al . Synergistic control of keratinocyte adhesion through muscarinic and nicotinic acetylcholine receptor subtypes.  Exp Cell Res. 2004;  294 534-549
• 39 Zouboulis CC, Boschnakow A. Chronological ageing and photoageing of the human sebaceous gland.  Clin Exp Dermatol. 2001;  26 600-607
• 40 Schafer T, Nienhaus A, Vieluf D, Berger J, Ring J. Epidemiology of acne in the general population: the risk of smoking.  Br J Dermatol. 2001;  145 100-104
• 41 Tretyn A, Kendrick RE. Acetylcholine in plants presence metabolism and mechanism of action.  Botan Rev. 1991;  57 33-73
• 42 Gupta R, Saxena RK, Goel S. Photoinduced sporulation in Trichoderma harzianum: an experimental approach to primary events.  World J Microbiol Biotechnol. 1997;  13 249-250
• 43 Buchli R, Ndoye A, Arredondo J, Webber RJ, Grando SA. Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes.  Mol Cell Biochem. 2001;  228 57-72
• 44 Zhao H, Boissy RE, Nordlung JJ. Down-regulation of human melanogenesis by acetylcholine in culture.  J Invest Dermatol. 1996;  106 910
• 45 Moller H, Lerner AB. Melanocyte stimulating hormone inhibition by acetylcholine and noradrenaline in the frog skin bioassay.  Acta Endocrinol. 1966;  51 149-160
• 46 Wallstrom M, Sand L, Nilsson F, Hirsch JM. The long-term effect of nicotine on the oral mucosa.  Addiction. 1999;  94 417-423
• 47 Gillbro JM, Marles LK, Hibberts NA, Schallreuter KU. Autocrine catecholamine biosynthesis and the beta-adrenoceptor signal promote pigmentation in human epidermal melanocytes.  J Invest Dermatol. 2004;  123 346-353
• 48 Warren JB. Nitric oxide and human skin blood flow responses to acetylcholine and ultraviolet light.  FASEB J. 1994;  8 247-251
• 49 Lewis T, Harris KE, Grant RT. Observations relating to the influence of the cutaneous nerves on various reactions of the cutaneous vessels.  Heart. 1927;  14 1-15
• 50 Kang-Rotondo CH, Major S, Chiang TM, Myers LK, Kang ES. Upregulation of nitric oxide synthase in cultured human keratinocytes after ultraviolet B and bradykinin.  Photoderm Photoimmunol Photomed. 1996;  12 57-65
• 51 Romero-Graillet C, Aberdam E, Clement M, Ortonne JP, Ballotti R. Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis.  J Clin Invest. 1997;  99 635-642
• 52 Sawada Y, Sakamaki T, Nakamura T, Sato K, Ono Z, Murata K. Release of nitric oxide in response to acetylcholine is unaltered in spontaneously hypertensive rats.  J Hypertens. 1994;  12 745-750
• 53 Iyengar B. Modulation of melanocytic activity by acetylcholine.  Acta Anat. 1989;  136 139-141
• 54 Chanco-Turner ML, Lerner AB. Physiologic changes in vitiligo.  Arch Dermatol. 1965;  91 390-396
• 55 Schallreuter KU, Elwary SM, Gibbons NC, Rokos H, Wood JM. Activation/deactivation of acetylcholinesterase by H₂O₂: more evidence for oxidative stress in vitiligo.  Biochem Biophys Res Commun. 2004;  315 502-508
• 56 Magnus IA, Thompson RHS. Cholinesterase activity of human skin.  Br J Dermatol. 1954;  66 163-173
• 57 Buchli R, Ndoye A, Rodriguez JG, Zia S, Webber RJ, Grando SA. Human skin fibroblasts express m2, m4, and m5 subtypes of muscarinic acetylcholine receptors.  J Cell Biochem. 1999;  74 264-277
• 58 Raposo G, Dunia I, Marullo S, Andre C, Guillet JG, Strosberg AD, Benedetti EL, Hoebeke J. Redistribution of muscarinic acetylcholine receptors on human fibroblasts induced by regulatory ligands.  Biology of the Cell. 1987;  60 117-123
• 59 Vestling M, Cowburn RF, Venizelos N, Lannfelt L, Winblad B, Adem A. Characterization of muscarinic acetylcholine receptors in cultured adult skin fibroblasts: effects of the Swedish Alzheimer's disease APP 670/671 mutation on binding levels.  J Neur Transm (Parkinson's Disease and Dementia Section). 1995;  10 1-10
• 60 Chew SJ, Lopez JG, Wilson R, Beuerman RW. Muscarinic antagonists inhibit the proliferation and EGF receptor expression of human ocular and NIH-3T3 fibroblasts.  Soc Neurosci Abstr. 1992;  18 927
• 61 Peacock ME, Sutherland DE, Schuster GS, Brennan WA, O'Neal RB, Strong SL, Van Dyke TE. The effect of nicotine on reproduction and attachment of human gingival fibroblasts in vitro.  J Periodontol. 1993;  64 658-665
• 62 Arredondo J, Hall LH, Ndoye A, Nguyen VT, Chernyavsky AI, Bercovich D, Orr-Urtreger A, Beaudet AL, Grando SA. Central role of fibroblast α3 nicotinic acetylcholine receptor in mediating cutaneous effects of nicotine.  Lab Invest. 2003;  83 207-225
• 63 Tipton DA, Dabbous MK. Effects of nicotine on proliferation and extracellular matrix production of human gingival fibroblasts in vitro.  J Periodontol. 1995;  66 1056-1064
• 64 Arredondo J, Nguyen VT, Chernyavsky AI, Bercovich D, Orr-Urtreger A, Vetter DE, Grando SA. Functional role of α7 nicotinic receptor in physiological control of cutaneous homeostasis.  Life Sci. 2003;  72 2063-2067
• 65 Frances C. Smoker's wrinkles: epidemiological and pathogenic considerations.  Clin Dermatol. 1998;  16 565-570
• 66 Conti-Fine BM, Navaneetham D, Lei S, Maus AD. Neuronal nicotinic receptors in non-neuronal cells: new mediators of tobacco toxicity?.  Eur J Pharmacol. 2000;  393 279-294
• 67 Raitio A, Vahakangas K, Haapasaari K-M, Risteli J, Oikarinen A. Smoking downregulates collagen synthesis in skin.  J Invest Dermatol. 1999;  113 452
• 68 Carty CS, Soloway PD, Kayastha S, Bauer J, Marsan B, Ricotta JJ, Dryjski M. Nicotine and cotinine stimulate secretion of basic fibroblast growth factor and affect expression of matrix metalloproteinases in cultured human smooth muscle cells.  J Vasc Surg. 1996;  24 27-35
• 69 Chamson A, Frey J, Hivert M. Effects of tobacco smoke extracts on collagen biosynthesis by fibroblast cell cultures.  J Toxicol Environ Health. 1982;  9 921-932
• 70 Yin L, Morita A, Tsuji T. Alterations of extracellular matrix induced by tobacco smoke extract.  Arch Dermatol Res. 2000;  292 188-194
• 71 Zia S, Ndoye A, Nguyen VT, Grando SA. Nicotine enhances expression of the α3, α4, α5, and α7 nicotinic receptors modulating calcium metabolism and regulating adhesion and motility of respiratory epithelial cells.  Res Commun Mol Pathol Pharmacol. 1997;  97 243-262
• 72 Arredondo J, Nguyen VT, Chernyavsky AI, Jolkovsky DL, Pinkerton KE, Grando SA. A receptor-mediated mechanism of nicotine toxicity in oral keratinocytes.  Lab Invest. 2001;  81 1653-1668
• 73 Grando SA, Horton RM, Mauro TM, Kist DA, Lee TX, Dahl MV. Activation of keratinocyte nicotinic cholinergic receptors stimulates calcium influx and enhances cell differentiation.  J Invest Dermatol. 1996;  107 412-418
• 74 Smith JB, Fenske NA. Cutaneous manifestations and consequences of smoking.  J Am Acad Dermatol. 1996;  34 717-732
• 75 Parnavelas JG, Kelly W, Burnstock G. Ultrastructural localization of choline acetyltransferase in vascular endothelial cells in rat brain.  Nature. 1985;  316 724-725
• 76 Kawashima K, Watanabe N, Oohata H, Fujimoto K, Suzuki T, Ishizaki Y, Morita I, Murota S. Synthesis and release of acetylcholine by cultured bovine arterial endothelial cells.  Neurosci Lett. 1990;  119 156-158
• 77 Kirkpatrick CJ, Bittinger F, Unger RE, Kriegsmann J, Kilbinger H, Wessler I. The non-neuronal cholinergic system in the endothelium: evidence and possible pathobiological significance.  Jap J Pharmacol. 2001;  85 24-28
• 78 Haberberger RV, Bodenbenner M, Kummer W. Expression of the cholinergic gene locus in pulmonary arterial endothelial cells.  Histochem Cell Biol. 2000;  113 379-387
• 79 Kirkpatrick CJ, Bittinger F, Nozadze K, Wessler I. Expression and function of the non-neuronal cholinergic system in endothelial cells.  Life Sci. 2003;  72 211-216
• 80 Ciani F, Franceschini V. Ultrastructural study and cholinesterase activity of paired capillaries in the new brain.  J Hirnforsch. 1984;  25 11-20
• 81 Lips KS, Pfeil U, Reiner K, Rimasch C, Kuchelmeister K, Braun-Dullaeus RC, Haberberger RV, Schmidt R, Kummer W. Expression of the high affinity choline transporter CHT1 in rat and human arteries.  J Histochem Cytochem. 2003;  51 1645-1654
• 82 Macklin KD, Maus AD, Pereira EF, Albuquerque EX, Conti-Fine BM. Human vascular endothelial cells express functional nicotinic acetylcholine receptors.  J Pharmacol Exp Ther. 1998;  287 435-439
• 83 Brüggmann D, Lips KS, Pfeil U, Haberberger RV, Kummer W. Rat arteries contain multiple nicotine acetylcholine receptor α-subunits.  Life Sci. 2003;  72 2095-2099
• 84 Abbruscato TJ, Lopez SP, Marks KS, Hawkins BT, Davis TP. Nicotine and cotonine modulate cerebral microvascular permeabilità and protein expression of ZO-1 through nicotinic acetylcholine receptors expressed on brain endothelial cells.  J Pharm Sci. 2002;  91 2525-2538
• 85 Moccia F, Frost C, Berra-Romani R, Tanzi F, Adams DJ. Expression and function of neuronal nicotinic receptors in rat microvascular endothelial cells.  Am J Physiol Heart Circ Physiol. 2004;  286 H486-H491
• 86 Hawkins BT, Egleton RD, Davis TP. Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors.  Am J Physiol Heart Circ Physiol. 2005;  289 H212-H219
• 87 Milner P, Kirkpatrick K, Ralevic V, Toothill V, Pearson J, Burnstock G. Endothelial cells cultured from umbilical vein release ATP, substance P, and acetylcholine in response to increased flow.  Proc R Soc Lond (Biol). 1990;  241 245-248
• 88 Albough G, Bellavance E, Strande L, Heinburger S, Hewitt CW, Alexander JB. Nicotine induces mononuclear leukocyte adhesion and expression of adhesion molecules, VCAM and ICAM, in endothelial cells in vitro.  Ann Vasc Surg. 2004;  18 302-307
• 89 Wang Y, Wang L, Ai X, Zhao J, Hao X, Lu Y, Qiao Z. Nicotine could augment adhesion molecule expression in human endothelial cells through macrophages secreting TNFα, IL-1β.  Int Immunopharmacol.. 2004;  4 1675-1686
• 90 Wang Y, Wang Z, Zhou Y, Liu L, Zhao Y, Yao C, Wang L, Qiao Z. Nicotine stimulates adhesion molecular expression via calcium influx and mitogen-activated protein kinases in human endothelial cells.  Int J Biochem Cell Biol.. 2006;  38 170-182
• 91 Saeed RW, Varma S, Peng-Nemeroff, Sherry B, Balakhaneh J, Tracey KJ, Al-Abed Y, Metz CN. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation.  JEM. 2005;  201 1113-1123
• 92 Chen YH, Chen SHM, Jong A, Zhou ZY, Li W, Suzuki K, Huang SH. Enhanced Escherichia coli invasion of human brain microvascular endothelial cells is associated with alternations in cytoskeleton induced by nicotine.  Cell Microbiol. 2002;  4 503-514
• 93 Tsai CH, Yeh HI, Tian TY, Lee YN, Lu CS, Ko YS. Down regulating effect of nicotine on connexin43 gap junctions in human umbilical vein endothelial cells is attenuated by statins.  Eur J Cell Biol. 2004;  82 589-595
• 94 Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, Tsao PS, Johnson FL, Cooke JP. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis.  Nature Med. 2001;  7 833-839
• 95 Heeschen C, Weis M, Aicher A, Dimmeler S, Cooke JP. A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors.  J Clin Invest. 2002;  110 527-536
• 96 Villablanca AC. Nicotine stimulates DNS synthesis and proliferation in vascular endothelial cells in vitro.  J Appl Physiol. 1998;  84 2089-2098
• 97 Kawashima K, Fujii T. Extraneuronal cholinergic system in lymphocytes.  Pharmacol Ther. 2000;  86 29-48
• 98 Hollis DE, Lyne AG. Acetylcholinesterase-positive langerhans cells in the epidermis and wool follicles of the sheep.  J Invest Dermatol. 1972;  58 211-217
• 99 Fujii T, Yamada S, Misawa H, Tajima S, Fujimoto K, Suzuki T, Kawashima K. Expression of choline acetyltransferase mRNA and protein in T-lymphocytes.  Proc Japan Acad. 1995;  71B 231-235
• 100 Kawashima K, Fujii T. Expression of non-neuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function.  Front Biosci. 2004;  9 2063-2085
• 101 Fujii T, Tsuchiya T, Yamada S, Fujimoto K, Suzuki T, Kasahara T, Kawashima K. Localization and synthesis of acetylcholine in human leukemic T-cell lines.  J Neurosci Res. 1996;  44 66-72
• 102 Tucek S. The synthesis of acetylcholine in skeletal muscles of the rat.  J Physiol (Lond). 1982;  322 53-69
• 103 Fujii T, Watanabe Y, Inoue T, Kawashima K. Up-regulation of mRNA encoding the M5 muscarinic acetylcholine receptor in human T- and B-lymphocytes during immunological responses.  Neurochem Res. 2003;  28 423-429
• 104 Fujii T, Ushiyama N, Hosonuma K, Suenaga A, Kawashima K. Effects of human antithymocyte globulin on acetylcholine synthesis, its release and choline acetyltransferase transcription in a human leukemic T-cell line.  J Neuroimmunol. 2002;  128 1-8
• 105 Fujii T, Kawashima K. Calcium oscillation is induced by muscarinic acetylcholine receptor stimulation in human leukemic T- and B-cell lines.  Naunyn-Schmiedberg's Arch Pharmacol. 2000;  362 14-21
• 106 Fuji T, Kawashima K. An independent non-neuronal cholinergic system in lymphocytes.  Jpn J Pharmacol. 2001;  85 11-15
• 107 Kawashima K, Fujii T. Minireview: The lymphocytic cholinergic system and its contribution to the regulation of immune activity.  Life Sci. 2003;  74 675-696
• 108 Kawashima K, Fuji T. The lymphocytic cholinergic system and its contribution to the regulation of immune activity.  Life Sci. 2003;  74 675-696
• 109 Zimring JC, Kapp LM, Yamada M, Wess J, Kapp JA. Regulation of CD8⁺ cytotoxic T lymphocyte differentiation by a cholinergic pathway.  J Immunol. 2005;  164 66-75
• 110 Albanesi C, Cavani A, Girolomoni G. Interferon-γ-stimulated human keratinocytes express the genes necessary for the production of peptide-loaded MHC-class II molecules.  J Invest Dermatol. 1998;  110 138-142
• 111 Weihe E, Nohr D, Michel S, Muller S, Zentel HJ, Fink T, Krekel J. Molecular anatomy of the neuro-immune connection.  Int J Neurosci. 1991;  59 1-23
• 112 Tracey KJ. The inflammatory reflex.  Nature. 2002;  420 ((6917)) 853-859
• 113 Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation.  Mol Med. 2003;  9 125-134
• 114 Sato E, Koyama S, Okubo Y, Kubo K, Sekiguchi M. Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity.  Am J Physiol. 1998;  274 L970-L979
• 115 Disse B. Antimuscarinic treatment for lung diseases from research to clinical practice.  Life Sci. 2001;  68 2557-2564
• 116 Razani-Boroujerdi S, Singh SP, Knall C, Hahn FF, Pena-Philippides JC, Kalra R, Langley RJ, Sopori ML. Chronic nicotine inhibits inflammation and promotes influenza infection.  Cell Immunol.. 2004;  230 1-9
• 117 Mamata Y, Hakki A, Yamamoto Y, Newton C, Klein TW, Pross S, Friedman H. Nicotine modulates cytokine production by Chlamydia pneumoniae infected human peripheral blood cells.  Int Immunopharmacol. 2005;  5 749-756
• 118 Wessler I, Deutsch C, Brockerhoff P, Bittinger F, Kirkpatrick CJ, Kilbinger H. Release of non-neuronal acetylcholine from the isolated human placenta is mediated by organic cation transporters.  Br J Pharmacol. 2001;  134 951-956
• 119 Koepsell H. Organic cation transporters in intestine, kidney, liver and brain.  Annu Rev Physiol. 1998;  60 243-266
• 120 Wessler I, Deutsch C, Bittinger F, Kirkpatrick CJ, Kilbinger H. Catecholamines inhibit the release of non-neuronal acetylcholine by substrate inhibition at the organic cation transporters.  Naunyn-Schmiedeberg's Arch Pharmacol. 2002;  365 ((Suppl)) R22
• 121 Alexander SPH, Mathie A, Peters JA. Guide to Receptors and Channels: 7 TM Receptors.  Br J Pharmacol. 2005;  144 4-62
• 122 Alexander SPH, Mathie A, Peters JA. Guide to receptors and channels: ion channels.  Br J Pharmacol. 2005;  144 73-94
• 123 Haddad EB, Patel H, Keeling JE, Yacoub MH, Barnes PJ, Belvisi MG. Pharmacological characterization of the muscarinic receptor antagonist, glycopyrrolate, in human and guinea-pig airways.  Br J Pharmacol. 1999;  127 413-420
• 124 Hayashi H, Fujii R. Pharmacological profiles of the subtypes of muscarinic cholinoceptors that mediate aggregation of pigment in the melanophores of two species of catfish.  Pigm Cell Res. 1994;  7 175-183

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