The sympathetic nerve - An integrative interface between two supersystems:The brain and the immune system

The brain and the immune system are the two major adaptive systems of the b ody. During an immune response the brain and the immune system "talk to eac h other" and this process is essential for maintaining homeostasis. Two maj or pathway systems are involved in this cross-talk: the hypothalamic-pituit ary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overv iew focuses on the role of SNS in neuroimmune interactions, an area that ha s received much less attention than the role of HPA axis. Evidence accumula ted over the last 20 years suggests that norepinephrine (NE) fulfills the c riteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, prima ry and secondary lymphoid organs receive extensive sympathetic/noradrenergi c innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenorecep tors. Through stimulation of these receptors, locally released NE, or circu lating catecholamines such as epinephrine, affect lymphocyte traffic, circu lation, and proliferation, and modulate cytokine production and the functio nal 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 neu ral input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epi nephrine, through stimulation of the beta (2)-adrenoreceptor-cAMP-protein k inase A pathway, inhibit the production of type 1/proinflammatory cytokines , such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon- gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they s timulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 respons es and cellular immunity, and a Th2 shift toward dominance of humoral immun ity. On the other hand, in certain local responses, and under certain condi tions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 product ion. Thus, the activation of SNS during an immune response might be aimed t o localize the inflammatory response, through induction of neutrophil accum ulation 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 produc ts of activated macrophages. The above-mentioned immunomodulatory effects o f catecholamines and the role of SNS are also discussed in the context of t heir clinical implication in certain infections, major injury and sepsis, a utoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is re viewed with focus on new therapeutic strategies using selective alpha (2)- and beta (2)-adrenoreceptor agonists and antagonists and inhibitors of phos phodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.