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The importance of beta-adrenergic receptors in immune regulation: a link between neuroendocrine and immune system
Medical Hypotheses (2001) 56(3), 273–276 © 2001 Harcourt Publishers Ltd doi: 10.1054/mehy.2000.1127, available online at http://www.idealibrary.com on
The importance of beta-adrenergic receptors in immune regulation: a link between neuroendocrine and immune system Biying Xu Department of Microbiology and Immunology, Georgetown University, Washington DC, USA
Summary Our knowledge of autoimmunity and autoimmune diseases has been advanced in the past decades. Receptors present on the immune cells may potentially regulate the immune system, among them, beta-adrenergic receptors are of special interest. As neurotransmitter receptors which are also present on lymphocytes, betaadrenergic receptors play an important role as the linkage of two important systems, neuroendocrine and immune systems. Here I summarize several lines of evidence of the importance of the beta-adrenergic receptors in immune regulation. © 2001 Harcourt Publishers Ltd
Beta-adrenergic receptors, including beta-1, beta-2 and beta-3 subtypes so far as we know, are glycoproteins that consist of 402–470 residues with a molecular weight around 64 Kd (1). They belong to the R7G family of Gprotein-coupled receptors. Beta-adrenergic receptors are found on a number of cell types, including skeletal muscle cells, cardiomyocytes, adipocytes and lymphocytes, the presence of the receptors on these tissues may have functional significance. Beta-adrenergic receptors on skeletal muscle are mainly of beta-2 subtype. They are important in regulation of plasma potassium level (2), muscle activities such as glycogenolysis (3) and contraction (4,5). Elevated epinephrine increases the intramuscular glycogen utilization, glycolysis and carbohydrate oxidation (6). The heart contains beta-1 and beta-2 subtypes that regulate both heart rate and contractile force. Changes in the numbers and affinity of the receptors have been found in several diseases, such as heart failure, idiopathic dilated cardiomyopathy and myocardial (7,8). Received 4 October 1999 Accepted 17 March 2000 Published online 23 January 2001 Correspondence to: Biying Xu, Department of Microbiology and Immunology, Georgetown University, Research Building W205, 3970 Reservoir Road NW, Washington DC, USA. Phone: +1 202 687 2143; Fax: +1 202 687 2221; E-mail: [email protected]
Would it surprise us those beta-receptors are associated with obesity and catecolamine can induce lipolysis in adipose tissues (9–11)? Changes of beta-adrenergic receptors have been found in several autoimmune diseases, such as multiple sclerosis (12,13), myasthenia gravis (14), rheumatoid arthritis (15,16), insulin-dependent diabetes mellitus (17,18). The finding of the presence of autoantibodies against beta-adrenergic receptors in myasthenia gravis patients demonstrates the immune response against the receptor and possible involvement in the disease (19). Although autoimmune disease is far more complicated as we know, e.g., multiple sclerosis and myasthenia gravis seemingly have different mechanisms behind, would there be certain common ground for all of them? The answer is supported by the observation that beta-2 receptor agonists can suppress the animal model of multiple sclerosis (EAE) (20), myasthenia gravis (EAMG) (21) arthritis (22) although the exact mechanisms were not clearly elucidated. The number of beta-adrenergic receptors and thus the regulation of the receptor differs on different mononuclear leukocytes (23) and lymphocyte subsets (24). Activation of beta-2 receptor leads to down-regulation of receptor density and generally the suppression of the immune reactions which include suppression of IL-2 receptor expression (25), inhibit lymphocyte proliferation and down-regulate cytokine production. The immunosuppressive effect of 273
274
Biying Xu
beta-2 agonists may be due to the elevation of cyclic AMP level. There is a growing body of evidence showing that an increase in cyclic AMP level results in inhibition of production of the Th1 type cytokines: IL-2 (26), IL-12 (27,28), IFNγ (29) and TNF-α (30,31), but stimulates the Th2 type cytokines: IL-4 (32), IL-5 (32,33), IL-6 (34) and IL-10 (35,36). It can also be due to the different expression of the receptor on Th1 and Th2 clones (37). Thus, ligation of betaadrenergic receptor leads to a shift toward a Th2 type of immune response, whereas down-regulation of intracellular cyclic AMP stimulates a Th1-type response. Another important factor which supports the importance of the beta-adrenergic receptor in immune regulation is the structure of their genes. GRE (glucocorticoid reactive elements) were found in the promoter of the genes. It was observed that glucocorticoid can up-regulate the beta-adrenergic receptor gene expression, while the maxim effect were found in beta-2 subtype as more GRE were found in its promoter region. Glucocorticoid that is commonly used for the treatment of autoimmune diseases as an immunosuppressive drug, which is an important factor of regulation the beta-receptor expression, indicates the potential importance of the receptor in immune regulation. Increasing studies on the gene polymorphism of beta-adrenergic receptors, so far were found in both beta-2 and beta-3 subtypes, have indicated the importance of them with association of certain diseases, such as asthma (38–41), hypertension (42), obesity (43), myasthenia gravis (44) and rheumatoid arthritis (manuscript in preparation). Although part of the association can be due to the receptor present on the target organ or tissue, it is striking to notice the association of certain polymorphism with certain disease subgroups, especially the association with the presence of antibodies. Besides, it is confirmed now by several independent studies that the gene polymorphisms of beta-2 adrenergic receptor are in linkage disequilibrium. It would be interesting and important to see whether these genes are in linkage with other genes on the same chromosomes, especially the gene encoding for beta-2 receptor located on chromosome 5 in which several important immune genes are located including IL-4, IL-3, GM-CSF. Could it be the reason that only activation of beta-2 adrenergic receptor which can result in the inhibition of IL-3, GM-CSF (45)? The question which fascinates me most is ‘why sympathetic nervous system dysfunction can be observed in most of the autoimmune diseases such as multiple sclerosis, myasthenia gravis, rheumatoid arthritis and IDDM?’ All these diseases are not seemingly related to each other, although they might present in certain patients at the same time. The beta-adrenergic receptors on lymphocytes represent the linkage between the autonomic nervous system and the immune system. A bi-directional communication exists between the nervous and the immune system. Medical Hypotheses (2001) 56(3), 273–276
The neurotransmitters, neuropeptides and hormones, can regulate functions of the immune system via specific receptors on its cells. On the other hand, cytokines that are released from immune cells may modulate sympathetic neuronal functions. It is now well established that immune cells can bind different neurotransmitters and neuropeptides, and that receptors for cytokines, such as IL-1 and others, are present on structures of the nervous system. Examples of these interactions are that cytokines produced by macrophages and lymphocytes, such as IL-1, IL2, IL-6 and TNF-α can inhibit NE release from presynaptic varicosities, in turn, the altered NE level might result in the changes of beta-adrenergic receptors which are its targets. It could affect the neurotransmitter release and nerve innervation by changed cyclic AMP level (46). Further, the changed beta-adrenergic receptor may exert its effect on the immune system according to different cell subsets. In addition, we may also take it into consideration the gene polymorphism of beta-adrenergic receptors (47). Could it be one of the factors contributing to the sympathetic nervous system dysfunction found in several autoimmune diseases? In addition, the regulation of beta-adrenergic receptor gene expression by glucocorticoid and cathecholamine being the main ligand for the receptor would further indicate the importance of neuroendocrine in immune regulation. The study of beta-adrenergic receptors may extend our knowledge on the subtle interaction between the two systems.
REFERENCES 1. Strosberg A. D. Structure/Function relationship of proteins belonging to the family of receptors coupled to GTP-binding proteins. Eur J Biochem 1991; 196: 1–10. 2. Elfellah M. S., Reid J. L. The role of skeletal muscle – β-adrenoceptors in the regulation of plasma potassium. J Auton Pharmac 1987; 7: 175–184. 3. Meyer S. E., Stull J. T. Cyclic AMP in skeletal muscle. Ann NY Acad Sci 1971; 185: 433–448. 4. Bowman W. C., Zamais E. The effects of adrenaline, noradrenaline and isoprenaline on skeletal muscle contractions in cat. J Physiol 1958; 144: 92. 5. Bowman W. C., Nott M. W. Actions of sympathomimetic amines and their antagonists on skeletal muscle. Pharmacol Rev 1969; 21: 27. 6. Febbraio M. A., Lambert D. L., Starkie R. L., Proietto J., Hargreaves M. Effect of epinephrine muscle glycogenolysis during exercise in trained men. J Appl Physiol 1998; 84: 465–470. 7. Insel P. A., Hammond H. K. β-adrenergic receptors in heart failure. J Clin Invest 1993; 92: 2564. 8. Gilbert E. M., Olsen S. L., Renlund D. G., Bristow M. R. Betaadrenergic receptor regulation and left ventricular function in idiopathic dilated cardiomyopathy. Am J Cardiol 1993; 71: 23C–29C. 9. Arner P., Hoffstedt J. Adrenoceptor genes in human obesity. J Intern Med 1999; 245: 667–672.
© 2001 Harcourt Publishers Ltd
Beta-adrenergic receptors in immune regulation
10. Large V., Hellstrom L., Reynisdottir S., Lonnqvist F., Eriksson F., Eriksson P., Lannfelt L., Arner P. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest 1997; 100: 3005–3013. 11. Hellstrom L., Wahrenberg H., Reynisdottir S., Arner P. Catecholamine-induced adipocyte lyolysis in human hyperthyroidism. J Clin Endocrinol Metab 1997; 82: 159–166. 12. Karaszewski J. W., Reder A. T., Anlar B., Kim W. C., Arnason B. G. W. Increased lymphocyte β-adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, CD28- suppressor cell. Ann Neurol 1991; 30: 42–47. 13. Zoukos Y., Leonard J. P., Thomaides T., Thompson A. J., Cuzner M. L. β-adrenergic receptor density and function of peripheral blood mononuclear cells are increased in multiple sclerosis: a regulatory role for cortisol and interleukin-1. Ann Neurol 1992; 31: 657–662. 14. Xu B. Y., Yi Q., Pirskanen R., Matell G., Hubert E., Lefvert A. K. Decreased β-adrenergic receptor density on peripheral blood mononuclear cells in myasthenia gravis. J. Autoimm 1997; 10: 401–406. 15. Baerwald C., Graefe C., von Wichert P., Krause A. Decreased density of β2-adrenergic receptors on peripheral blood mononuclear cells in patients with rheumatoid arthritis. J Rheumatol 1992; 19: 204–209. 16. Krause A., Henrich A., Beckh K. H., von Wichert P., Baerwald C. Correlation between density of 2-adrenergic receptors on peripheral blood mononuclear cells and serum levels of soluble interleukin-2 receptors in patients with chronic inflammatory diseases. Eur J Clin Invest 1992; 22(Suppl. 1): 47–51. 17. Noji T., Tashiro M., Yaji H., Nagashima K., Suzuki S., Kuroume T. Adaptive regulation of β-adrenergic receptors in children with insulin dependent diabetes mellitus. Horm Metabol Res 1986; 18: 604–606. 18. Schwab K. O., Bartels H., Martin C., Leichtenschlag E. M. Decreased β2-adrenoceptor density and decreased isoproterenol induced c-AMP increase in juvenile type I diabetes mellitus: an additional cause of severe hypoglycemia in childhood diabetes? Eur J Pediatr 1993; 152: 797–801. 19. Xu B. Y., Pirskanen R., Lefvert A. K. Antibodies against beta-1 and beta-2 adrenergic receptors in myasthenia gravis. J Neuroimmunol 1998; 91: 82–88. 20. Wiegmann K., Muthyala S., Kim D. H., Arnason B. G., Chelmicka-Schorr E. Beta-adrenergic agonists suppress chronic/relapsing experimental allergic encephalomyelitis (CREAE) in Lewis rats. J Neuroimmunol 1995; 56: 201–206. 21. Chelmicka-Schorr E., Wollmann R. L., Kwasniewski M. N., Kim D. H., Dupont B. L. The beta 2-adrenergic agonist terbutaline suppresses acute passive transfer experimental autoimmune myasthenia gravis (EAMG). Int J Immunopharmacol 1993; 15: 19–24. 22. Malfait A. M., Malik A. S., Marinova-Mutafchieva L., Butler D. M., Maini R. N., Feldmann M. The beta2-adrenergic agonist salbutamol is a potent suppressor of established collageninduced arthritis: mechanisms of action. J Immunol 1999; 162: 6278–6283. 23. Maisel A. S., Fowler P., Rearden A., Motulsky J., Michel M. C. A new method for isolation of human lymphocyte subsets reveals differential regulation of β-adrenergic receptors by terbutaline treatment. Clin Pharmacol Ther 1989; 46: 429–439. 24. Khan M. M., Sansoni P., Silverman E. D., Engleman E. G., Melmon K. L. Beta-adrenergic receptors on human suppressor, helper, and cytolytic lymphocytes. Biochem Pharmacol 1986; 35: 1137–1142.
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25. Feldman R. D., Hunninghake G. W., McArdle W. L. β-adrenergic receptor-mediated suppression of interleukin 2 receptors in human lymphocytes. J Immunol 1987; 139: 3355–3359. 26. Sekut L., Champion B. R., Page K., Menius J. R., Connolly K. M. Anti-inflammatory activity of salmeterol: down-regulation of cytokine production. Clin Exp Immunol 1995; 99: 461–466. 27. van der Pouw Kraan T. C. T. M., Boeije L. C. M., Smeenk R. J. T., Wijdenes J., Aarden L. Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. J Exp Med 1995; 181: 775–779. 28. Aloisi F., Penna G., Cerase J., Iglesias B. M., Adorini L. IL-12 production by central nervous system microglia is inhibited by astrocytes. J Immunol 1997; 159: 1604–1612. 29. Ivashkiv L. B., Ayres A., Glimcher L. H. Inhibition of IFN-γ induction of class II MHC genes by cyclic AMP and prostaglandins. Immunopharmacology 1994; 27: 67–77. 30. Katakami Y., Nakao Y., Koizumi Y., Katakami N., Ogawa R., Fujita T. Regulation of tumour necrosis factor production by mouse peritoneal macrophages: the role of cellular cyclic AMP. Immunology 1988; 64: 719–724. 31. Renz H., Gong J-H., Scmidt A., Nain M., Gemsa D. Release of tumor necrosis factor-α from macrophages enhancement of suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol 1988; 141: 2388–2393. 32. Lacour M., Arrighi J-F., Muller K. M., Carlberg C., Saurat J-H., Hauser C. Cyclic AMP up-regulates IL-4 and IL-5 production from activated CD4+ T cells while decreasing IL-2 release and NF-AT induction. Int Immunol 1994; 6: 1333–1343. 33. Siegel M. D., Zhang D-H., Ray P., Ray A. Activation of the interleukin-5 promoter by cyclic AMP in murine EL-4 cells requires the GATA-3 and CLE0 elements. J Biol Chem 1995; 270: 24548–24555. 34. Zhang Y. H., Lin J-X., Vilcek J. Synthesis of interleukin 6 (interferon-β2/B cell stimulatory factor 2) in human fibroblasts is triggered by an increase in intracellular cyclic AMP. J Biol Chem 1988; 263: 6177–6182. 35. Platzer C., Meisel C., Vogt K., Platzer M., Volk H-D. Upregulation of monocytic IL-10 by tumour necrosis factor-α and cyclic AMP elevating drugs. Int Immunology 1995; 7: 517–523. 36. Eigler A., Siegmund B., Emmerich U., Baumann K. H., Hartmann G., Endres S. Anti-inflammatory activities of cyclic AMPelevating agents: enhancement of IL-10 synthesis and concurrent suppression of TNF production. J Leukocyte Biol 1998; 63: 101–107. 37. Sander V. M., Baker R. A., Ramer-Quinn D. S., Kasprowicz D. J., Fuchs B. A., Street N. E. Differential expression of the beta2adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol 1997; 158: 4200–4210. 38. Liggett S. B. Genetics of β2-adrenergic receptor variants in asthma. Clin Exp Allergy 1995; 25: 89–94. 39. Liggett S. B. Polymorphisms of the 2-adrenergic receptor and asthma. Am J Respir Crit Care Med 1997; 156: S156–S162. 40. Reihsaus E., Innis M., MacIntyre N., Liggett S. B. Mutations in the gene encoding for the 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993; 8: 334–339. 41. Tan S., Hall I. P., Dewar J., Dow E., Lipworth B. Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350: 995–999. 42. Svetkey L. P., Timmons P. Z., Emovon O., Anderson N. B., Preis L., Chen Y-T. Association of hypertension with β2- and α2c10adrenergic receptor genotype. Hypertension 1996; 27: 1210–1215.
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43. Large V., Hellstrom L., Reymisdottir S., Lpnnqvist F., Eriksson P., Lannfelt L., Arner P. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest 1997; 100: 3005–3013. 44. Xu B. Y., Huang D. R., Pirskanen R., Lefvert A. K. β2-adrenergic receptor gene polymorphisms in myasthenia gravis. Clin Exp Immunol 2000; 119: 156–160. 45. Borger P., Hoekstra Y., Esselink M. T., Postma D. S., Zaagsma J., Vellenga E., Kauffman H. Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF m RNA accumulation in activated human T lymphocytes is solely mediated by the
Medical Hypotheses (2001) 56(3), 273–276
beta2-adrenoceptor subtype. Am J Respir Cell Mol Biol 1998; 19: 400–407. 46. Cheung U. S., Shayan A. J., Boulianne G. L., Atwood H. L. Drosophila larval neuromuscular junction’s responses to reduction of cyclic AMP in the nervous system. J Neurobiol 1999; 40: 1–13. 47. Shihara N., Yasuda K., Moritani T., Ue H., Adachi T., Tanaka H., Tsuda K., Seino Y. The association between Trp64Arg Polymorphism of the beta3-adrenergic receptor and autonomic nervous system activity. J Clin Endocrinol Metab 1999; 84: 1623–1627.
© 2001 Harcourt Publishers Ltd
The importance of beta-adrenergic receptors in immune regulation: a link between neuroendocrine and immune system Biying Xu Department of Microbiology and Immunology, Georgetown University, Washington DC, USA
Summary Our knowledge of autoimmunity and autoimmune diseases has been advanced in the past decades. Receptors present on the immune cells may potentially regulate the immune system, among them, beta-adrenergic receptors are of special interest. As neurotransmitter receptors which are also present on lymphocytes, betaadrenergic receptors play an important role as the linkage of two important systems, neuroendocrine and immune systems. Here I summarize several lines of evidence of the importance of the beta-adrenergic receptors in immune regulation. © 2001 Harcourt Publishers Ltd
Beta-adrenergic receptors, including beta-1, beta-2 and beta-3 subtypes so far as we know, are glycoproteins that consist of 402–470 residues with a molecular weight around 64 Kd (1). They belong to the R7G family of Gprotein-coupled receptors. Beta-adrenergic receptors are found on a number of cell types, including skeletal muscle cells, cardiomyocytes, adipocytes and lymphocytes, the presence of the receptors on these tissues may have functional significance. Beta-adrenergic receptors on skeletal muscle are mainly of beta-2 subtype. They are important in regulation of plasma potassium level (2), muscle activities such as glycogenolysis (3) and contraction (4,5). Elevated epinephrine increases the intramuscular glycogen utilization, glycolysis and carbohydrate oxidation (6). The heart contains beta-1 and beta-2 subtypes that regulate both heart rate and contractile force. Changes in the numbers and affinity of the receptors have been found in several diseases, such as heart failure, idiopathic dilated cardiomyopathy and myocardial (7,8). Received 4 October 1999 Accepted 17 March 2000 Published online 23 January 2001 Correspondence to: Biying Xu, Department of Microbiology and Immunology, Georgetown University, Research Building W205, 3970 Reservoir Road NW, Washington DC, USA. Phone: +1 202 687 2143; Fax: +1 202 687 2221; E-mail: [email protected]
Would it surprise us those beta-receptors are associated with obesity and catecolamine can induce lipolysis in adipose tissues (9–11)? Changes of beta-adrenergic receptors have been found in several autoimmune diseases, such as multiple sclerosis (12,13), myasthenia gravis (14), rheumatoid arthritis (15,16), insulin-dependent diabetes mellitus (17,18). The finding of the presence of autoantibodies against beta-adrenergic receptors in myasthenia gravis patients demonstrates the immune response against the receptor and possible involvement in the disease (19). Although autoimmune disease is far more complicated as we know, e.g., multiple sclerosis and myasthenia gravis seemingly have different mechanisms behind, would there be certain common ground for all of them? The answer is supported by the observation that beta-2 receptor agonists can suppress the animal model of multiple sclerosis (EAE) (20), myasthenia gravis (EAMG) (21) arthritis (22) although the exact mechanisms were not clearly elucidated. The number of beta-adrenergic receptors and thus the regulation of the receptor differs on different mononuclear leukocytes (23) and lymphocyte subsets (24). Activation of beta-2 receptor leads to down-regulation of receptor density and generally the suppression of the immune reactions which include suppression of IL-2 receptor expression (25), inhibit lymphocyte proliferation and down-regulate cytokine production. The immunosuppressive effect of 273
274
Biying Xu
beta-2 agonists may be due to the elevation of cyclic AMP level. There is a growing body of evidence showing that an increase in cyclic AMP level results in inhibition of production of the Th1 type cytokines: IL-2 (26), IL-12 (27,28), IFNγ (29) and TNF-α (30,31), but stimulates the Th2 type cytokines: IL-4 (32), IL-5 (32,33), IL-6 (34) and IL-10 (35,36). It can also be due to the different expression of the receptor on Th1 and Th2 clones (37). Thus, ligation of betaadrenergic receptor leads to a shift toward a Th2 type of immune response, whereas down-regulation of intracellular cyclic AMP stimulates a Th1-type response. Another important factor which supports the importance of the beta-adrenergic receptor in immune regulation is the structure of their genes. GRE (glucocorticoid reactive elements) were found in the promoter of the genes. It was observed that glucocorticoid can up-regulate the beta-adrenergic receptor gene expression, while the maxim effect were found in beta-2 subtype as more GRE were found in its promoter region. Glucocorticoid that is commonly used for the treatment of autoimmune diseases as an immunosuppressive drug, which is an important factor of regulation the beta-receptor expression, indicates the potential importance of the receptor in immune regulation. Increasing studies on the gene polymorphism of beta-adrenergic receptors, so far were found in both beta-2 and beta-3 subtypes, have indicated the importance of them with association of certain diseases, such as asthma (38–41), hypertension (42), obesity (43), myasthenia gravis (44) and rheumatoid arthritis (manuscript in preparation). Although part of the association can be due to the receptor present on the target organ or tissue, it is striking to notice the association of certain polymorphism with certain disease subgroups, especially the association with the presence of antibodies. Besides, it is confirmed now by several independent studies that the gene polymorphisms of beta-2 adrenergic receptor are in linkage disequilibrium. It would be interesting and important to see whether these genes are in linkage with other genes on the same chromosomes, especially the gene encoding for beta-2 receptor located on chromosome 5 in which several important immune genes are located including IL-4, IL-3, GM-CSF. Could it be the reason that only activation of beta-2 adrenergic receptor which can result in the inhibition of IL-3, GM-CSF (45)? The question which fascinates me most is ‘why sympathetic nervous system dysfunction can be observed in most of the autoimmune diseases such as multiple sclerosis, myasthenia gravis, rheumatoid arthritis and IDDM?’ All these diseases are not seemingly related to each other, although they might present in certain patients at the same time. The beta-adrenergic receptors on lymphocytes represent the linkage between the autonomic nervous system and the immune system. A bi-directional communication exists between the nervous and the immune system. Medical Hypotheses (2001) 56(3), 273–276
The neurotransmitters, neuropeptides and hormones, can regulate functions of the immune system via specific receptors on its cells. On the other hand, cytokines that are released from immune cells may modulate sympathetic neuronal functions. It is now well established that immune cells can bind different neurotransmitters and neuropeptides, and that receptors for cytokines, such as IL-1 and others, are present on structures of the nervous system. Examples of these interactions are that cytokines produced by macrophages and lymphocytes, such as IL-1, IL2, IL-6 and TNF-α can inhibit NE release from presynaptic varicosities, in turn, the altered NE level might result in the changes of beta-adrenergic receptors which are its targets. It could affect the neurotransmitter release and nerve innervation by changed cyclic AMP level (46). Further, the changed beta-adrenergic receptor may exert its effect on the immune system according to different cell subsets. In addition, we may also take it into consideration the gene polymorphism of beta-adrenergic receptors (47). Could it be one of the factors contributing to the sympathetic nervous system dysfunction found in several autoimmune diseases? In addition, the regulation of beta-adrenergic receptor gene expression by glucocorticoid and cathecholamine being the main ligand for the receptor would further indicate the importance of neuroendocrine in immune regulation. The study of beta-adrenergic receptors may extend our knowledge on the subtle interaction between the two systems.
REFERENCES 1. Strosberg A. D. Structure/Function relationship of proteins belonging to the family of receptors coupled to GTP-binding proteins. Eur J Biochem 1991; 196: 1–10. 2. Elfellah M. S., Reid J. L. The role of skeletal muscle – β-adrenoceptors in the regulation of plasma potassium. J Auton Pharmac 1987; 7: 175–184. 3. Meyer S. E., Stull J. T. Cyclic AMP in skeletal muscle. Ann NY Acad Sci 1971; 185: 433–448. 4. Bowman W. C., Zamais E. The effects of adrenaline, noradrenaline and isoprenaline on skeletal muscle contractions in cat. J Physiol 1958; 144: 92. 5. Bowman W. C., Nott M. W. Actions of sympathomimetic amines and their antagonists on skeletal muscle. Pharmacol Rev 1969; 21: 27. 6. Febbraio M. A., Lambert D. L., Starkie R. L., Proietto J., Hargreaves M. Effect of epinephrine muscle glycogenolysis during exercise in trained men. J Appl Physiol 1998; 84: 465–470. 7. Insel P. A., Hammond H. K. β-adrenergic receptors in heart failure. J Clin Invest 1993; 92: 2564. 8. Gilbert E. M., Olsen S. L., Renlund D. G., Bristow M. R. Betaadrenergic receptor regulation and left ventricular function in idiopathic dilated cardiomyopathy. Am J Cardiol 1993; 71: 23C–29C. 9. Arner P., Hoffstedt J. Adrenoceptor genes in human obesity. J Intern Med 1999; 245: 667–672.
© 2001 Harcourt Publishers Ltd
Beta-adrenergic receptors in immune regulation
10. Large V., Hellstrom L., Reynisdottir S., Lonnqvist F., Eriksson F., Eriksson P., Lannfelt L., Arner P. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest 1997; 100: 3005–3013. 11. Hellstrom L., Wahrenberg H., Reynisdottir S., Arner P. Catecholamine-induced adipocyte lyolysis in human hyperthyroidism. J Clin Endocrinol Metab 1997; 82: 159–166. 12. Karaszewski J. W., Reder A. T., Anlar B., Kim W. C., Arnason B. G. W. Increased lymphocyte β-adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, CD28- suppressor cell. Ann Neurol 1991; 30: 42–47. 13. Zoukos Y., Leonard J. P., Thomaides T., Thompson A. J., Cuzner M. L. β-adrenergic receptor density and function of peripheral blood mononuclear cells are increased in multiple sclerosis: a regulatory role for cortisol and interleukin-1. Ann Neurol 1992; 31: 657–662. 14. Xu B. Y., Yi Q., Pirskanen R., Matell G., Hubert E., Lefvert A. K. Decreased β-adrenergic receptor density on peripheral blood mononuclear cells in myasthenia gravis. J. Autoimm 1997; 10: 401–406. 15. Baerwald C., Graefe C., von Wichert P., Krause A. Decreased density of β2-adrenergic receptors on peripheral blood mononuclear cells in patients with rheumatoid arthritis. J Rheumatol 1992; 19: 204–209. 16. Krause A., Henrich A., Beckh K. H., von Wichert P., Baerwald C. Correlation between density of 2-adrenergic receptors on peripheral blood mononuclear cells and serum levels of soluble interleukin-2 receptors in patients with chronic inflammatory diseases. Eur J Clin Invest 1992; 22(Suppl. 1): 47–51. 17. Noji T., Tashiro M., Yaji H., Nagashima K., Suzuki S., Kuroume T. Adaptive regulation of β-adrenergic receptors in children with insulin dependent diabetes mellitus. Horm Metabol Res 1986; 18: 604–606. 18. Schwab K. O., Bartels H., Martin C., Leichtenschlag E. M. Decreased β2-adrenoceptor density and decreased isoproterenol induced c-AMP increase in juvenile type I diabetes mellitus: an additional cause of severe hypoglycemia in childhood diabetes? Eur J Pediatr 1993; 152: 797–801. 19. Xu B. Y., Pirskanen R., Lefvert A. K. Antibodies against beta-1 and beta-2 adrenergic receptors in myasthenia gravis. J Neuroimmunol 1998; 91: 82–88. 20. Wiegmann K., Muthyala S., Kim D. H., Arnason B. G., Chelmicka-Schorr E. Beta-adrenergic agonists suppress chronic/relapsing experimental allergic encephalomyelitis (CREAE) in Lewis rats. J Neuroimmunol 1995; 56: 201–206. 21. Chelmicka-Schorr E., Wollmann R. L., Kwasniewski M. N., Kim D. H., Dupont B. L. The beta 2-adrenergic agonist terbutaline suppresses acute passive transfer experimental autoimmune myasthenia gravis (EAMG). Int J Immunopharmacol 1993; 15: 19–24. 22. Malfait A. M., Malik A. S., Marinova-Mutafchieva L., Butler D. M., Maini R. N., Feldmann M. The beta2-adrenergic agonist salbutamol is a potent suppressor of established collageninduced arthritis: mechanisms of action. J Immunol 1999; 162: 6278–6283. 23. Maisel A. S., Fowler P., Rearden A., Motulsky J., Michel M. C. A new method for isolation of human lymphocyte subsets reveals differential regulation of β-adrenergic receptors by terbutaline treatment. Clin Pharmacol Ther 1989; 46: 429–439. 24. Khan M. M., Sansoni P., Silverman E. D., Engleman E. G., Melmon K. L. Beta-adrenergic receptors on human suppressor, helper, and cytolytic lymphocytes. Biochem Pharmacol 1986; 35: 1137–1142.
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