Some Aspects of the Normal Role of Neuromodulators in the Immune System
John Smythies
DOI: 10.4236/nm.2011.23035   PDF    HTML     6,875 Downloads   11,159 Views   Citations


This review covers recent advances in our knowledge of the role of a group of the most prominent neurotransmitters and neuromodulators in the field of the immune reactions of the body. The neurotransmitters and neuromodulators covered are the three catecholamines (epinephrine, noradrenaline and dopamine), serotonin, acetylcholine (both nicotinic and muscarinic functions), and histamine.

Share and Cite:

J. Smythies, "Some Aspects of the Normal Role of Neuromodulators in the Immune System," Neuroscience and Medicine, Vol. 2 No. 3, 2011, pp. 275-281. doi: 10.4236/nm.2011.23035.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] T. Hori, T. Katafuchi, S. Take, N. Shimizu and A. Nijima. “The Autonomic Nervous System as a Communication Channel between the Brain and the Immune System,” Neuroimmunomodulation, Vol. 2, No. 4, 1995, pp. 203- 215.
[2] K. Yasunari, T. Matsui, K. Maeda, M. Nakamura, T. Watanabe and N. Kiriike, “Anxiety-Induced Plasma Norepinephrine Augmentation Increases Reactive Oxygen Species Formation by Monocytes in Essential Hypertension,” American Journal of Hypertension, Vol. 19, No. 6, 2006, pp. 573-578. doi:10.1016/j.amjhyper.2005.10.027
[3] A. Bierhaus, J. Wolf, M. Andrasy, P. M. Rohleder, P. M. Humpert. D. Petrov, R. Fersti, M. von Eynatten, T. Wendt, G. Rudofsky, M. Joswig, M. Morcos, M. Schwaniger, B. McEwan, C. Kirschbaum and P. P. Nawroth, “A Mechanism Converting Psychosocial Stress into Mononuclear Cell Activation,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 4, 2003, pp. 1920-1925, Epub 2003 Feb 10. doi:10.1073/pnas.0438019100
[4] F. McKenna, P. J. McLaughlin, B. J. Lewis, G. C. Sibbring, J. A. Cummerson, D. Bowen-Jones and R. J. Moots, “Dopamine Receptor Expression on Human T- and B-lymphocytes, Monocytes, Neutrophils, Eosinophils and NK Cells: A Flow Cytometric Study,” Journal of Immunology, Vol. 132, No. 1, 2002, pp. 34-40. doi:10.1016/0192-0561(94)90045-0
[5] H. M. Shen, L. X. Sha, J. L. Kennedy and D. W. Ou, “Adrenergic Receptors Regulate Macrophage Secretion,” International Journal of Immunopharmacology, Vol. 16, No. 11, 1994, pp. 905-910.
[6] M. M. Khan, P. Sansoni, E. D. Silverman, E. G. Engleman and K. L. Melmon, “Beta-Adrenergic Receptors on Human Suppressor, Helper, and Cytolytic Lymphocytes,” Biochemical Pharmacology, Vol. 35, No. 7, 1986, pp. 1137-1142. doi:10.1016/0006-2952(86)90150-4
[7] T. Yukawa, D. Ukena, C. Kroegel, P. Chanez, G. Dent, K. F. Chung and P. J. Barnes. “Beta 2-Adrenergic Receptors on Eosinophils. Binding and Functional Studies,” American Review of Respiratory Diseases, Vol. 141, No. 6, 1990, pp. 1446-1452.
[8] J. W. Hadden, E. M. Hadden and E. Middelton Jr, “Lymphocyte Blast Transformation. I. Demonstration of Adrenergic Receptors in Human Peripheral Lymphocytes,” Cell Immunology, Vol. 1, No. 6, 1970, pp. 583- 595. doi:10.1016/0008-8749(70)90024-9
[9] E. Pállinger and G. Csaba, “Presence and Distribution of Biogenic Amines (Histamine, Serotonin and Epinephrine) in Immunophenotyped Human Immune Cells,” Inflammation Research, Vol. 57, No. 11, 2008, pp. 530-534.
[10] S. W. Brown, R. T. Meyers, K. M. Brennan, J. M. Rumble, N. Narasimhachari, E. F. Perozzi, J. J. Ryan, J. K. Stewart and K. Fischer-Stenger, “Catecholamines in a Macrophage Line,” Journal of Immunology, Vol. 135, No. 1-2, 2003, pp. 47-55.
[11] M. Cosentino, R. Bombelli, M. Ferrari, F. Marino, E. Rasini, G. J. Naestroni, A. Conti, M. Boveri, S. Lecchini and G. Frigo, “HPLC-ED Measurement of Endogenous Catecholamines in Human Immune Cells and Hematopoietic Cell Lines,” Life Sciences, Vol. 68, No. 3, 2000, pp. 283-295. doi:10.1016/S0024-3205(00)00937-1
[12] M. Ferrari, M. Cosentino, F. Marino, R. Bombelli, S. Lecchini and G. Frigo, “Dopaminergic D1-Like Receptor- Dependent Inhibition of Tyrosine Hydroxylase mRNA Expression and Catecholamine Production in Human Lymphocytes,” Biochemical Phamacology, Vol. 67, No. 5, 2004, pp. 865-873.
[13] G. Leposavic, I . Pilipovic, K. Radojevic, V. Pesic, M. Perisic and D. Kosec, “Catecholamines as Immunomodulators: A Role for Adrenoceptor-Mediated Mechanisms in Fine Tuning of T-Cell Development,” Autonomic Neuroscience, Vol. 144, No. 1, 2008, pp. 1-12, Epub 2008 October 30. doi:10.1016/j.autneu.2008.09.003
[14] S. Dimitrov, T. Lange and J. Born, “Selective Mobilization of Cytotoxic Leukocytes by Epinephrine,” Journal of Immunology, Vol, 184, No. 1, 2010, pp. 503-511, Epub 2009 November 30. doi:10.4049/jimmunol.0902189
[15] O. Rohr, B. E. Sawaya, D. Lecestre, D. Aunis and E. Schaeffer, “Dopamine Stimulates Expression of the Human Immunodeficiency Virus Type 1 via NF-kappaB in Cells Of The Immune System,” Nucleic Acids Research, Vol. 27, No. 16, 1999, pp. 3291-3299. doi:10.1093/nar/27.16.3291
[16] L. A. Grisanti, J. Evanson, E. Marchus, H. Jorissen, A. P. Woster, W. DeKrey, E. R. Sauter, C. K. Combs and J. E. Porter, “Pro-Inflammatory Responses in Human Monocytes Are Beta1-Adrenergic Receptor Subtype Dependent,” Molecular Immunology, Vol. 47, No. 6, 2010, pp. 1244-1254, Epub 2010 January 29. doi:10.1016/j.molimm.2009.12.013
[17] J. D. Lünemann, F. Buttgereit, R. Tripmacher, C. G. Baerwald, G. R. Burmester and A. Krause, “Norepineph- rine Inhibits Energy Metabolism of Human Peripheral Blood Mononuclear Cells via Adrenergic Receptors,” Bioscience Reports, Vol. 21, No. 5, 2002, pp. 627-635.
[18] H. K. Takahashi, S. Mori, K. Liu, H. Wake, J. Zhang, R. Liu, T. Yoshino and M. Nishibori, “Beta2-Adrenoceptor Stimulation Inhibits Advanced Glycation End Products- Induced Adhesion Molecule Expression and Cytokine Production in Human Peripheral Blood Mononuclear Cells,” European Journal of Pharmacology, Vol. 627, No. 1-3, 2010, pp. 313-317, Epub 2009 October 24. doi:10.1016/j.ejphar.2009.10.034
[19] U. Riese, S. Brenner, W. D. D?cke, S. Pr?sch, P. Reinke, M. Oppert, H. D. Volk and C. Platzer, “Catecholamines Induce IL-10 Release in Patients Suffering from Acute Myocardial Infarction by Transactivating Its Promoter In Monocytic but Not in T-Cells,” Molecular and Cellular Biochemistry, Vol. 212, No. 1, 2000, pp. 45-50. doi:10.1023/A:1007196602659
[20] S. K. Agarwal and G. D. Marshall Jr, “Beta-Adrenergic Modulation of Human Type-1/Type-2 Cytokine Balance,” Journal of Allergy and Clinical Immunology, Vol. 105, Part 1, 2000, pp. 91-98. doi:10.1016/S0091-6749(00)90183-0
[21] R. Landmann. “Beta-Adrenergic Receptors in Human Leukocyte Subpopulations,” European Journal of Clinical Investigation, Vol. 22, Suppl. 1, 1992, pp. 30-36.
[22] L. Santambrogio, M. Liparti, A. Bruni and R. Dal Toso, “Dopamine Receptors on Human T- and B- Lymphocytes,” Journal of Neuroimmunology, Vol. 45, No. 1-2, 1993, pp. 113-119. doi:10.1016/0165-5728(93)90170-4
[23] Y. H. Qiu, Y. P. Peng, J. M. Jiang and J. J. Wang, “Expression of Tyrosine Hydroxylase in Lymphocytes and Effect of Endogenous Catecholamines on Lymphocyte Function,” Neuroimmunomodulation, Vol. 11, No. 1, 2004, pp. 75-83.
[24] N. R. Musso, S. Brenci, M. Setti, F. Indiveri and G. Lotti. “Catecholamine Content and in Vitro Catecholamine Synthesis in Peripheral Human Lymphocytes,” Journal of Clinical Endocrinology and Metabolism, Vol. 81, 1996, pp. 3553-3557. doi:10.1210/jc.81.10.3553
[25] E. J. Essman. “Serotonin Receptors on Pulmonary Alveolar Macrophages,” Ric Clinic Laboratories, Vol. 15, No. 1, 1985. pp. 19-24.
[26] O. Fajardo, J. Galeno, M. Urbina, I. Carreira and L. Lima, “Serotonin, Serotonin 5-HT(1A) Receptors And Dopamine in Blood Peripheral Lymphocytes of Major Depression Patients,” International Immunopharmacology, Vol. 3, No. 9, 2003, pp. 1345-1352. doi:10.1016/S1567-5769(03)00116-4
[27] S. A. Boehme, F. M. Lio, L. Sikora, T. S. Pamdit, K. Lavrador, S. P. Rao and P. Sriramarao, “Cutting Edge: Serotonin Is a Chemotactic Factor for Eosinophils and Functions Additively with Eotaxin,” Journal of Immunology, Vol. 173, No. 6, pp. 3599-3603.
[28] R. M?ssner and K. P. Lesch, “Role of Serotonin in the Immune System and in Neuroimmune Interactions,” Brain Behavior and Immunity, Vol. 12. No.4, pp. 249- 271.
[29] J. C. Jackson, R. F. Walker, W. H. Brooks and T. L. Roszman, “Specific Uptake of Serotonin by Murine Macrophages,” Life Sciences, Vol. 42, No. 17, 1988, pp. 203-215. doi:10.1016/0024-3205(88)90443-2
[30] E. M. Sternberg, H. J. Wedner, M. K. Leung and C. W. Parker, M. Rosas-Ballina and K. J. Tracey, “Effect of Serotonin (5-HT) and Other Monoamines on Murine Macrophages: Modulation of the Interferon-Gamma Induced Phagocytosis,” Journal of Immunology, Vol. 138, No. 12, 1987, pp. 4360-4365.
[31] Z. Mikulski, Z. Zaslona. L. Cakarova, P. Hartmann, J. Wilhelm, L. H. Tecott, J. Lohmayer and W. Kummer, “Serotonin Activates Murine Alveolar Macrophages through 5-HT2C Receptors,” American Journal of Physiology Lung Cellular and Molecular Physiology, Vol. 299, No. 2, pp. L272-280, Epub 2010 May 21.
[32] S. Sanchez, S. D. Paredes, C. L. Sanchez, C. Barriga, R. J. Reiter and A. B. Rodruigez, “Tryptophan Administration in Rats Enhances Phagocytic Function and Reduces Oxidative Metabolism,” Neuroendocrinology Letters, Vol. 29, No. 6, 2008, pp. 1026-1032.
[33] M. L. Rudd, A. N. Nicolas, B. L. Brown, K. Fischer- Stenger and J. K. Stewart, “Peritoneal Macrophages Ex- press the Serotonin Transporter,” Neuroimmunology, Vol. 159, No. 1-2, 2005, pp. 113-118, Epub 2004 Nov 25.
[34] M. Freire-Garabal, M. J. Nú?ez, J. Balboa, P. López- Delgado, R. Gallego, T. García-Caballero, M. D. Fernán- dez-Roel, J. Brenlla and M. Rey-Méndez, “Serotonin Upregulates the Activity of Phagocytosis through 5-Ht1a Receptors,” British Journal of Pharmacology, Vol. 139, No. 2, 2003, pp. 457-463. doi:10.1038/sj.bjp.0705188
[35] A. Nocito, F. Dahm, W. Jochum, J. H. Jang, P. Georgiev, M. Bader, R. Graf and P. A. Clavien, “Serotonin Regulates Macrophage-Mediated Angiogenesis in a Mouse Model of Colon Cancer Allografts,” Cancer Research, Vol. 68, No. 13, No. 10, pp. 5152-5158.
[36] G. Ménard, V. Turmel and E. Y. Bissonnette, “Serotonin Modulates the Cytokine Network In The Lung: Involvement of Prostaglandin E2,” Clinical and Experimental Immunology, Vol. 150, No. 2, 2007, pp. 340-348.
[37] M. Kubera, M. Maes, G. Kenis, Y. K. Kim and W. Lason, “Effects of Serotonin and Serotonergic Agonists and Antagonists on the Production of Tumor Necrosis Factor Alpha and Interleukin-6,” Psychiatry Research, Vol. 134, No. 3, 2005. pp. 251-258. doi:10.1016/j.psychres.2004.01.014
[38] D. J. Kodomerkos, S. A. Kalamidas and O. B. Kotoulas, “In Vitro Effects of Hormones and Autacoids on the Hydrogen Peroxide Production and the Morphology of Endotoxin-Activated Rat Peritoneal Macrophages,” Histology and Histopathology, Vol, 18, No. 1, 1988, pp. 203- 215.
[39] M. R. Young and J. P. Matthews, “Serotonin Regulation of T-Cell Subpopulations and of Macrophage Accessory Function,” Immunology, Vol. 84, No. 1, 1995, pp. 148- 152.
[40] G. P. Ahern. “5-HT and the Immune System,” Current Opinion in Pharmacology, 2011 March 8, [Epub ahead of print].
[41] R. Pacheco, E. Riquelme and M. Kalergis, “Emerging Evidence for the Role of Neurotransmitters in the Modulation of T Cell Responses to Cognate Ligands,” Central Nervous System Agents in Medicinal Chemistry, Vol. 10, No. 1, 2010, pp. 65-83.
[42] I. Wessler, C. J Kirkpatrick and K. Racké, “The Cholinergic ‘Pitfall’: Acetylcholine, a Universal Cell Molecule in Biological Systems, Including Humans,” Clinical and Experimental Pharmacology and Physiology, Vol. 26, No. 3, 1999, pp. 198-205. doi:10.1046/j.1440-1681.1999.03016.x
[43] I. Clo?z-Tayarani and J. P. Changeux. “Nicotine and Serotonin in Immune Regulation and Inflammatory Processes: A Perspective,” Journal of Leukocyte Biology, Vol. 81, No. 3, 2007, pp. 599-606, Epub 2006 Nov 1.
[44] C. R. Gwilt, L. E. Donnelly and D. F. Rogers, “The Non- Neuronal Cholinergic System in the Airways: An Unappreciated Regulatory Role in Pulmonary Inflammation?” Pharmacology and Therapeutics, Vol. 115, No. 2, 2007, pp. 208-222, Epub 2007 May 25. doi:10.1016/j.pharmthera.2007.05.007
[45] S. L. Oke and K. J. Tracey, “From CNI-1493 to the Immunological Homunculus: Physiology of the Inflammatory Reflex,” Journal of Leukocyte Biology, Vol. 83, No. 3, 2008, pp. 512-517, Epub 2007 Dec 7. doi:10.1189/jlb.0607363
[46] M. Rosas-Ballina and K. J. Tracey, “The Neurology of the Immune System: Neural Reflexes Regulate Immunity,” Neuron, Vol. 64, No, 1, 2009, pp. 28-32.
[47] D. Giuliani, A. Ottani, D. Altavilla, C. Bazzani, F. Squadrito and S. Guarini, “Melanocortins and the Cholinergic Anti-Inflammatory Pathway,” Advances in Experimental and Medical Biology, Vol. 681, 2010, pp. 71- 87. doi:10.1007/978-1-4419-6354-3_6
[48] H. Wang, M. Yu, M. Ochani, C. A. Amelia, M. Tanovic, S. Susaria, J. H. Li, H. Wang, H. Yang, L. Ulloa, Y. Al-Abed, C. J. Czura, and K. J. Tracey, “Nicotinic Acetylcholine Receptor Alpha7 Subunit Is an Essential Regulator of Inflammation,” Nature, Vol. 421 , No. 6921, pp. 384-388, Epub 2002 December 22.
[49] H. Yoshikawa, M. Kurakowa, N. Ozaki, K. Nara, K. Atou, E. Takada, H. Kamochi and N. Sazuki, “Nicotine Inhibits the Production of Proinflammatory Mediators in Human Monocytes by Suppression of I-kappaB Phosphorylation and Nuclear Factor-kappaB Transcriptional Activity through Nicotinic Acetylcholine Receptor Alpha7,” Cli- nical and Experimental Immunology, Vol. 146, No. 1. 2006, pp. 116-123.
[50] X. Wang, Z. Yang, B. Xue and H. Shi, “Activation of the Cholinergic Antiinflammatory Pathway Ameliorates Obesity-Induced Inflammation and Insulin Resistance,” Endocrinology, Vol. 152, No. 3, 2011, pp. 836-846, Epub 2011 Jan 14.
[51] A. I. Chernavasky, J. Arredondo, M. Skok and S. A. Grando, “Auto/Paracrine Controlof Inflammatory Cytokines by Acetylcholine in Macrophage-Like U937 Cells Through Nicotinic Receptors,” International Immunopharmacology, Vol. 10, No. 3, 2010, pp. 308-315, Epub 2009 December 18.
[52] K. Whaley, D. Lappin and T. Barkas, “C2 Synthesis by Human Monocytes Is Modulated by a Nicotinic Cholinergic Receptor,” Nature, Vol. 293, No. 5833, 1981, pp. 580-583.
[53] M. R. Blanchet, A. Langlois, E. Isra?l-Assayag, M. J. Beaulieu, C. Ferland, M. Laviolette and Y. Cormier. “Modulation of Eosinophil Activation in Vitro by a Nicotinic Receptor Agonist,” Journal of Leukocyte Biology, Vol. 81, No. 5, 2007, pp. 1245-1251, Epub 2007 Feb 8.
[54] Y. Tsuchida, F. Hatao, M. Fujisawa, T. Murata, M. Kaminishi, Y. Seto, M. Hori and H. Ozaki, “Neuronal Stimulation with 5-Hydroxytryptamine 4 Receptor Induces Anti-Inflammatory Actions via {Alpha}7nACh Receptors on Muscularis Macrophages Associated with Postoperative Ileus,” Gut, Vol. 60, No.5, 2011, pp. 638-647, Epub 2010 November 29.
[55] G. Zhang, A. L. Thomas, A. L. Marshall, K. A. Kernan, Y. Su, Y. Zheng, J. Takano, T. C. Saido and A. A. Eddy, “Nicotinic Acetylcholine Receptor α1 Promotes Calpain-1 Activation and Macrophage Inflammation in Hypercholesterolemic Nephropathy,” Laboratory Investigations, Vol. 91, No.1, 2011, pp. 106-123, Epub 2010 Jul 26.
[56] Z. Mikulski, P. Hartmann, G. Jositsch, Z. Zastona, K. S. Lips. U. Pfeil, H. Kurzen, J. Lohmeyer, W. G. Clauss, V. Grau, M. Fronius and W. Kummer, “Nicotinic Receptors on Rat Alveolar Macrophages Dampen ATP-Induced Increase in Cytosolic Calcium Concentration,” Respiration Research, Vol. 11, No. 1, 2010a, pp. 133-156. doi:10.1186/1465-9921-11-133
[57] A. Lopker, L. G. Abood, W. Hoss and F. J. Lionetti, Stereoselective Muscarinic Acetylcholine and Opiate Receptiors in Human Phagocytic Leukocytes, Biochemical Pharmacology, Vol. 29, No. 10, 1980, pp. 1361-1365. doi:10.1016/0006-2952(80)90431-1
[58] R. Gosens, J. Zaagsma, H. Meurs and A. J. Halayko, “Muscarinic Receptor Signaling in the Pathophysiology of Asthma and COPD,” Respiratory Research, Vol. 7, No. 1, 2006, pp. 73-79.
[59] C. Wallon, M. Persborn, M. J?nsson, A. Wang, V. Phan, M. Lampinen, M. Vicario, J. Santos, P. M. Sherman, M. Carlson, A. C. Ericson, D. M. McKay and J.,D. S?derholm, “eosinophils Express Muscarinic Receptors and Corticotropin-Releasing Factor to Disrupt the Mucosal Barrier In Ulcerative Colitis,” Gastroenterology, Vol. 140, No. 5, 2011, pp. 1597-1607, Epub 2011 January 26.
[60] E. de la Torre, A. M. Genaro, M. L. Ribeiro, R. Pagetto and M. E. Sales, “Proliferative Actions of Muscarinic Receptors Expressed in Macrophages Derived from Normal and Tumor Bearing Mice,” Biochimica Biophysica Acta, Vol. 1782, No. 2, 2008, pp. 82-89, Epub 2007 Nov 22.
[61] Z. Nie, G. D. Scott, P. D. Weiss, A. Itakura, A. D. Fryer and D. B. Jacoby, “Role of TNF-α in Virus-Induced Airway Hyperresponsiveness and Neuronal M(2) Muscarinic Receptor Dysfunction,” British Journal of Pharmacology, 2011 April 1, [Epub ahead of print]. doi:10.1111/j.1476-5381.2011.01393.x.
[62] E. Schneider, N. Thieblemont, M. L. De Moraes and M. Dy, “Basophils: New Players in the Cytokine Network,” European Cytokine Network, Vol. 21, No. 3, 2010, pp. 142-153.
[63] K. F?rber, U. Pannasch and H. Kettenmann, “Dopamine and Noradrenaline Control Distinct Functions in Rodent Microglial Cells,” Molecular and Cellular Neuroscience, Vol. 29, No. 1, 2005, pp. 128-138.
[64] J. Y. Chang and L. Z. Liu. “Catecholamines Inhibit Microglial Nitric Oxide Production,” Brain Research Bulletin, Vol. 52, No. 6, 2000, pp. 525-530. doi:10.1016/S0361-9230(00)00291-4

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.