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Review ArticleReview

The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System

Ilia J. Elenkov, Ronald L. Wilder, George P. Chrousos and E. Sylvester Vizi
Pharmacological Reviews December 2000, 52 (4) 595-638;
Ilia J. Elenkov
1Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland (I.J.E., R.L.W.); 2Pediatric Endocrinology Section, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (I.J.E., G.P.C.); 3Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary (E.S.V.); and 4Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (E.S.V.)
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Ronald L. Wilder
1Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland (I.J.E., R.L.W.); 2Pediatric Endocrinology Section, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (I.J.E., G.P.C.); 3Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary (E.S.V.); and 4Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (E.S.V.)
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George P. Chrousos
1Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland (I.J.E., R.L.W.); 2Pediatric Endocrinology Section, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (I.J.E., G.P.C.); 3Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary (E.S.V.); and 4Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (E.S.V.)
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E. Sylvester Vizi
1Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland (I.J.E., R.L.W.); 2Pediatric Endocrinology Section, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (I.J.E., G.P.C.); 3Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary (E.S.V.); and 4Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (E.S.V.)
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Abstract

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system “talk to each other” and this process is essential for maintaininghomeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the β2-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-α, and interferon-γ by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-β. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-α, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective α2- and β2-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

Footnotes

  • ↵1 Address for correspondence: Dr. E. Sylvester Vizi, Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, P.O. Box 67, Hungary. E-mail: esvizi{at}koki.hu

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Pharmacological Reviews: 52 (4)
Pharmacological Reviews
Vol. 52, Issue 4
1 Dec 2000
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Review ArticleReview

The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System

Ilia J. Elenkov, Ronald L. Wilder, George P. Chrousos and E. Sylvester Vizi
Pharmacological Reviews December 1, 2000, 52 (4) 595-638;

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Review ArticleReview

The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System

Ilia J. Elenkov, Ronald L. Wilder, George P. Chrousos and E. Sylvester Vizi
Pharmacological Reviews December 1, 2000, 52 (4) 595-638;
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  • Article
    • Abstract
    • I. Introduction
    • II. Anatomy and Physiology of the Autonomic Nervous System
    • III. Autonomic/Sympathetic Innervation of Lymphoid Organs: Nonsynaptic Communication
    • IV. Nonsynaptic Release of Norepinephrine in Lymphoid Organs: Presynaptic Modulation and Effect of Drugs
    • V. Systemic and Local Effects of Cytokines on Sympathetic Nervous System Activity
    • VI. Expression of Adrenoreceptors on Lymphoid Cells: Signal Transduction
    • VII. Role of Sympathetic Innervation in Immune System Development and Hematopoiesis
    • VIII. Sympathetic Control of Lymphocyte Traffic and Circulation
    • IX. Modulation of Lymphocyte Proliferation and K+Channel Conductance
    • X. Modulation of cellular and humoral immunity by catecholamines
    • XI. Role of Growth Factors in Sympathetic Nervous System Development and Modulation of the Immune Response
    • XII. Physiologic Control of the Sympathetic-Immune Interface: β-Adrenergic Receptor Expression, Coupling, and Desensitization
    • XIII. Clinical Implications
    • XIV. Pharmacological Manipulation of the Sympathetic-Immune Interface
    • XV. Conclusions
    • Footnotes
    • Abbreviations
    • References
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