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 maintaining homeostasis 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 beta(2)-adrenoreceptor-cAMP-protein kinase 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 stimulate 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 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-alpha, 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 alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome

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

Turnbull, Andrew V., and Catherine L. Rivier. Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action. Physiol. Rev. 79: 1–71, 1999. — Glucocorticoids a...

Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action

The body's early defence in response to trauma, inflammation or infection, the acute phase response, is a complex set of systemic reactions seen shortly after exposure to a triggering event. One of the many components is an acute phase protein response in which increased hepatic synthesis leads to increased serum concentration of positive acute phase proteins. The serum concentration of these acute phase proteins returns to base levels when the triggering factor is no longer present. This paper provides a review of the acute phase proteins haptoglobin, C-reactive protein and serum amyloid A and their possible use as non-specific indicators of health in large animal veterinary medicine such as in the health status surveillance of pigs at the herd level, for the detection of mastitis in dairy cattle and for the prognosis of respiratory diseases in horses.

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Application of acute phase protein measurements in veterinary clinical chemistry.

Cytokine-to-brain communication: A review & analysis of alternative mechanisms

If cytokines are constitutively expressed by and act on neurons in normal adult brain, then we may have to modify our current view that they are predominantly inflammatory mediators. We critically reviewed the literature to determine whether we could find experimental basis for such a modification. We focused on two "proinflammatory" cytokines, interleukin (IL)-1 and tumor necrosis factor-alpha (TNFalpha) because they have been most thoroughly investigated in shaping our current thinking. Evidence, although equivocal, indicates that the genes coding for these cytokines and their accessory proteins are expressed by neurons, in addition to glial cells, in normal brain. Their expression is region- and cell type-specific. Furthermore, bioactive cytokines have been extracted from various regions of normal brain. The cytokines' receptors selectively are present on all neural cell types, rendering them responsive to cytokine signaling. Blocking their action modifies multiple neural "housekeeping" functions. For example, blocking IL-1 or TNFalpha by several independent means alters regulation of sleep. This indicates that these cytokines likely modulate in the brain behavior of a normal organism. In addition, these cytokines are likely involved in synaptic plasticity, neural transmission, and Ca2+ signaling. Thus, the evidence strongly suggests that these cytokines perform neural functions in normal brain. We therefore propose that they should be thought of as neuromodulators in addition to inflammatory mediators.

"Inflammatory" cytokines: neuromodulators in normal brain?

To examine the effects of brain cytokines on the sympathetic nervous system, norepinephrine (NE) turnover in peripheral organs (spleen, lung, diaphragm, pancreas, heart, liver, kidney, and interscapular brown adipose tissue) was assessed after intraperitoneal or intracerbroventricular administrations of human recombinant interleukin (IL)-1 beta and IL-6 in rats. An intraperitoneal injection of IL-1 (1 microgram/rat) accelerated NE turnover in the spleen, lung, diaphragm, and pancreas without appreciable effects in other organs examined. When IL-1 was injected intracerebroventricularly at much lower doses (1-100 ng/rat), a dose-dependent increase in NE turnover was observed in the spleen, lung, diaphragm, and pancreas. IL-6 did not affect NE turnover in every organ examined, even when it was given at much higher doses, 100 micrograms/rat and 100 ng/rat for intraperitoneal and intracerebroventricular injections, respectively. In contrast to tissue NE turnover, plasma corticosterone level was increased after the administration of IL-6 as well as IL-1, regardless of the site of administration. These results suggest that central IL-1, but not IL-6, increases sympathetic nerve activity in some specific organs, whereas both cytokines are effective for adrenocortical activation. A possible role of the sympathetic nervous system in physiological and immune responses to central IL-1 was discussed.

Tissue-specific increase in norepinephrine turnover by central interleukin-1, but not by interleukin-6, in rats

Cytokine-induced change in hypothalamic norepinephrine turnover: involvement of corticotropin-releasing hormone and prostaglandins

Induction of acute phase protein by recombinant human interleukin-6 (IL-6) in calves.

Possible roles of prostaglandins (PGs) in interleukin-1 (IL-1)-induced activation of noradrenergic neurons were examined by assessing norepinephrine (NE) turnover in the brain and peripheral organs of rats. An intraperitoneal injection of human recombinant IL-1β accelerated NE turnover in the hypothalamus, spleen, lung, diaphragm, and pancreas. A similar increase in NE turnover was also observed after intracerebroventricular injection of corticotropin-releasing hormone (CRH). Pretreatment with indomethacin (cyclooxygenase inhibitor) abolished the IL-1-induced, but not the CRH-induced, increase in hypothalamic and splenic NE turnover. To elucidate which eicosanoid-cyclooxygenase product(s) is responsible for accelerating NE turnover, PGD 2 , PGE 2 , PGF 2α , U-46619 (stable thromboxane A 2 analogue), or carbacyclin (stable prostacyclin analogue) was administered intracerebroventricularly. Among them, PGE 2 was the only eicosanoid effective in increasing NE turnover in spleen, whereas PGD 2 was effective in the hypothalamus. The stimulative effect of PGD 2 was abolished by pretreatment with intracerebroventricular injection of a CRH antiserum. These results suggest that the action of IL-1 is mediated through PGD 2 production to activate the noradrenergic neurons in the hypothalamus, and through PGE 2 production to increase sympathetic nerve activity in spleen.

Roles of Prostaglandins D2 and E2 in Interleukin‐1‐Induced Activation of Norepinephrine Turnover in the Brain and Peripheral Organs of Rats

To examine the possible role of brain IL-6 in the acute phase response, plasma iron and corticosterone levels were measured after intraperitoneal and intracerebroventricular injections of interleukin-1β (IL-1) and interleukin-6 (IL-6) in rats. An intraperitoneal injection of IL-1 and IL-6 increased plasma corticosterone level and decreased iron level. Although intracerebroventricular infection of IL-1 mimicked both responses in much lower doses, IL-6 was effective only on corticosterone response. It was suggested that brain IL-6 is involved in, if any, only a part of the acute phase response

Masayuki Saito

Papers

Tissue-specific increase in norepinephrine turnover by central interleukin-1, but not by interleukin-6, in rats

Cytokine-induced change in hypothalamic norepinephrine turnover: involvement of corticotropin-releasing hormone and prostaglandins

Induction of acute phase protein by recombinant human interleukin-6 (IL-6) in calves.

Roles of Prostaglandins D2 and E2 in Interleukin‐1‐Induced Activation of Norepinephrine Turnover in the Brain and Peripheral Organs of Rats

Possible role of IL-6 in IL-1-induced plasma iron and corticosterone responses in rats